Serine protease inhibitors

ABSTRACT

Compounds of formula (I) 
                         
where R 5 , R 6a , each X, L, Cy and Lp are as defined in the specification, are tryptase inhibitors useful as antiinflammatory agents.

This application is a divisional of application Ser. No. 10/148,174, nowU.S. Pat. No. 6,916,957 which is a 371 of PCT/GB00/04764 filed Dec. 13,2000.

This invention relates to compounds which are inhibitors of the serineprotease, tryptase, to pharmaceutical compositions thereof and to theiruse in the treatment of the human or animal body. More particularly itrelates to compounds for use in the treatment of mast cell mediateddiseases such as asthma and other allergic and inflammatory conditions,to pharmaceutical compositions thereof and to their use in the treatmentof the human or animal body.

Asthma, the most prevalent of all mast cell mediated conditions affectsabout 5% of the population in industrialised countries and there isevidence that its incidence and severity are on the increase.Furthermore, the incidence of childhood asthma is rising and there aresuggestions of a link between environmental pollutants and the onset ofthe disease.

Initially, it was believed that bronchoconstriction, i.e. the narrowingof the airways in the lungs, was the major feature of asthma. However,it is now recognised that inflammation in the lungs is an integral partof the development of the disease.

The inhalation of an allergen by an asthmatic generates a strong immunesystem response which triggers release of various inflammatorymediators, including histamine and leukotrienes from inflammatory cells.These increase the permeability of the blood vessel walls, attractinflammatory cells into the tissues and contract the smooth musclearound the airways. As a result, fluid leaks from the blood and thetissues swell, further narrowing the airways. The inflammatory cellscause damage to the epithelial cells lining the airways exposing nerveendings which stimulates secretion of mucous as well as augmenting theinflammation by causing the release of neurokinins.

Thus asthma is a complex disease frequently characterised by progressivedevelopments of hyper-responsiveness of the trachea and bronchi as aresult of chronic inflammation reactions which irritate the epitheliumlining the airway and cause pathological thickening of the underlyingtissues.

Leukocytes and mast cells are present in the epithelium and smoothmuscle tissue of the bronchi where they are activated-initially bybinding of specific inhaled antigens to IgE receptors. Activated mastcells release a number of preformed or primary chemical mediators of theinflammatory response in asthma as well as enzymes. Moreover, secondarymediators of inflammation are generated by enzymatic reactions ofactivated mast cells and a number of large molecules are released bydegranulation of mast cells.

It has therefore been proposed that chemical release from mast cellsprobably accounts for the early bronchiolar constriction response thatoccurs in susceptible individuals after exposure to airborne allergens.The early asthmatic reaction is maximal at around 15 minutes afterallergen exposure, recovery occurring over the ensuing 1 to 2 hours. Inapproximately 30% of individuals, the early asthmatic reaction isfollowed by a further decline in respiratory function which normallybegins within a few hours and is maximal between 6 and 12 hours afterexposure. This late asthmatic reaction is accompanied by a markedincrease in the number of inflammatory cells infiltrating bronchiolarsmooth muscle and epithelial tissues, and spilling into the airways.These cells are attracted to the site by release of mast cell derivedchemotactic agents.

The most straightforward way of dealing with an asthma attack is with abronchodilator drug which causes airways to expand. The most effectivebronchodilators are the β-adrenergic agonists which mimic the actions ofadrenalin. These are widely used and are simply administered to thelungs by inhalers. However, bronchoconstrictor drugs are primarily ofuse in short term symptomatic relief, and do not prevent asthma attacksnor deterioration of lung function over the long term.

Anti-inflammatory drugs such as cromoglycate and the corticosteroids arealso widely used in asthma therapy. Cromoglycate has anti-inflammatoryactivity and has been found to be extremely safe. Although suchcromolyns have minimal side effects and are currently preferred forinitial preventive therapy in children, it is well known that they areof limited efficacy.

The use of corticosteroids in asthma therapy was a major advance sincethey are very effective anti-inflammatory agents, however, steroids arevery powerful, broad spectrum anti-inflammatory agents and their potencyand non-specificity means that they are seriously limited by adverseside effects.

Localising steroid treatment to the lungs using inhaler technology hasreduced side effects but the reduced systemic exposure followinginhalation still results in some undesirable effects. Hence, there is areluctance to use steroids early in the course of the disease.

There therefore still remains a need for an alternative asthma therapywhich is a safe, effective, anti-inflammatory or immunomodulatory agentwhich can be taken to treat chronic asthma.

Tryptase is the major secretory protease of human mast cells and isproposed to be involved in neuropeptide processing and tissueinflammation. Tryptase is one of a large number of serine proteaseenzymes which play a central role in the regulation of a wide variety ofphysiological processes including coagulation, fibrinolysis,fertilization, development, malignancy, neuromuscular patterning andinflammation. Although a large number of serine proteases have beenwidely investigated, tryptase still remains relatively unexplored.

Mature human tryptase is a glycosylated, heparin-associated tetramer ofcatalytically active subunits. Its amino-acid structure appears to haveno close counterpart among the other serine proteases which have beencharacterised. Tryptase is stored in mast cell secretory granules andafter mast cell activation, human tryptase can be measured readily in avariety of biological fluids. For example, after anaphylaxis, tryptaseappears in the blood stream where it is readily detectable for severalhours. Tryptase also appears in samples of nasal and lung lavage fluidfrom atopic subjects challenged with specific antigen. Tryptase has beenimplicated in a variety of biological processes where activation anddegranulation of mast cells occur. Accordingly, mast cell tryptaseinhibition may be of great value in the prophylaxis and treatment of avariety of mast cell mediated conditions. Mast cells can degranulate byboth IgE-dependent and independent mechanisms thereby implicatingtryptase in both atopic and non-atopic inflammatory conditions. Tryptasecan activate proteases such as pro-urokinase and pro-MMP3 (pro-matrixmetalloprotease 3, pro-stromelysin), thereby indicating a pathologicalrole in tissue inflammation and remodelling. Furthermore, the recentevidence that tryptase can activate certain G-protein coupled receptors(eg PAR2) and induce neurogenic inflammation points to a broaderphysiological role, for example in modulating pain mechanisms. Giventryptase's multiple mechanisms of action, it has been proposed thattryptase inhibitors may be beneficial in a broad range of diseases.These include conditions such as: asthma (specifically influencing theinflammatory component, the underlying hyperreactivity, and the chronicfibrotic damage due to smooth muscle thickening); chronic obstructivepulmonary disease (COPD) and pulmonary fibrotic diseases; rhinitis;psoriasis; urticaria; dermatitis; arthritis; Crohn's disease; colitis;angiogenesis; atherosclerosis; multiple sclerosis; interstitialcystitis; migraine headache; neurogenic inflammation and painmechanisms; wound healing; cirrhosis of the liver; Kimura's disease;pre-eclampsia; bleeding problems associated with menstruation and themenopause; cancer (particularly melanoma and tumour metastasis);pancreatitis; and certain viral infections (Yong, Exp. Toxic Pathol,1997, 49, 409; Steinhoff et al., Nat. Med., 2000, 6, 151; Downing andMiyan, Immunol. Today, 2000, 21, 281; Tetlow and Wooley, Ann. Rheum.Dis., 1995, 54, 549; Jeziorska, Salamonsen and Wooley, Biol. Reprod.,1995, 53, 312; Brain, Nat. Med., 2000, 6, 134; Olness et al., Headache,1999, 39, 101.) The underlying principle is that a tryptase inhibitorshould have utility where mast cells have being induced to degranulateby whatever mechanism, including anaphylactic reactions due to exogenoussubstances, e.g. morphine-induced bronchoconstriction (Bowman and Rand,Textbook of Pharmacology, 2^(nd) edt., 1980.)

In WO96/09297, WO95/32945, WO94/20527 and U.S. Pat. No. 5,525,623 avariety of peptide based compounds are suggested as potential inhibitorsof the mast cell protease tryptase. In WO95/03333 a tryptase inhibitoris provided by a polypeptide obtainable from the leech hirudomedicinalis. In WO96/08275 secretory leukocyte protease inhibitor (SLPI)and active fragments thereof have been found to inhibit the proteolyticactivity of tryptase. In WO99/55661 certain 4-aminomethylbenzoic esterderivatives are proposed as potential tryptase inhibitors.

We have now found that certain aromatic compounds carrying lipophilicside chains are particularly effective as inhibitors of the serineprotease, tryptase.

It is envisaged that the compounds of the invention will be useful notonly in the treatment and prophylaxis of asthma but also of otherallergic and inflammatory conditions mediated by tryptase such asallergic rhinitis, skin conditions such as eczema, psoriasis, atopicdermatitis and urticaria, rheumatoid arthritis, conjunctivitis,inflammatory bowel disease, neurogenic inflammation, atherosclerosis andcancer.

Thus viewed from one aspect the invention provides a tryptase inhibitorcompound of formula (I)

where:

R₅ represents amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen;

R_(6a) represents hydrogen or methyl;

X—X is selected from —CH═CH—, —CONR_(1a)—, —NH—CO—, —NR_(1a)—CH₂—,—CH₂—NR_(1a)—, —CH₂O—, —OCH₂—, —COO—, —OC═O— and —CH₂CH₂—;

R_(1a) represents hydrogen, (1–6C)alkyl or phenyl(1–6C)alkyl;

L is CO or CONR_(1d)(CH₂)_(m) in which m is 0 or 1 and R_(1d) ishydrogen, (1–6C)alkyl or phenyl(1–6C)alkyl;

Cy is a saturated or unsaturated, mono or poly cyclic, homo orheterocyclic group, preferably containing 5 to 10 ring atoms andoptionally substituted by one or more groups R_(3a)— or R_(3i)X_(I)—;

each R_(3a) independently is hydrogen, hydroxyl, (1–6C)alkoxy,(1–6C)alkyl, (2–6C)alkenyl, (2–6C)alkynyl, (1–6C)alkanoyl,(1–6C)alkylaminoalkyl, hydroxy(1–6C)alkyl, carboxy, (1–6C)alkoxyalkyl,(1–6C)alkoxycarbonyl, (1–6C) alkylaminocarbonyl, amino(1–6C)alkyl CONH₂,CH₂CONH₂, aminoacetyl, (1–6C)alkanoylamino, (1–6C)alkoxycarbonylamino,amino, halo, cyano, nitro, thiol, (1–6C)alkylthio, (1–6C)alkylsulphonyl, (1–6C)alkylsulphenyl, imidazolyl, hydrazido,(1–6C)alkylimidazolyl, (1–6C)alkylsulphonamido, (1–6C)alkylaminosulphonyl, aminosulphonyl, (1–6C) haloalkoxy, or (1–6C)haloalkyl;

X_(i) is a bond, O, NH or CH₂; and R_(3i) is phenyl optionallysubstituted by R_(3a);

provided that the compound of formula I is not3-aminomethylbenzoyl-D-phenylglycine-4-aminomethylcyclohexyl-methylamideor 3-aminomethylbenzoyl-D-phenylglycine-1-adamantylamide;

or a physiologically tolerable salt thereof, e.g. a halide, phosphate orsulphate salt or a salt with ammonium or an organic amine such asethylamine or meglumine.

Compounds of formula I have surprisingly been found to be particularlyeffective as inhibitors of tryptase and to show a surprising selectivityfor tryptase over other serine proteases.

In the compounds of the invention, R₅ preferably represents amino orhydrogen, more preferably hydrogen.

R_(6a) preferably represents hydrogen.

In the compounds of the invention, the alpha atom (*) preferably has theconformation that would result from construction from a D-α-aminoacidNH₂—CH(Cy)-COOH where the NH₂ represents part of X—X.

In the compounds of the invention, unless otherwise indicated, arylgroups preferably contain 5 to 10 ring atoms optionally including 1, 2or 3 heteroatoms selected from O, N and S; alkyl, alkenyl or alkynylgroups or alkylene moieties preferably contain up to 6 carbons, e.g.C₁₋₆ or C₁₋₃; cyclic groups preferably have ring sizes of 3 to 8 atoms;and fused multicyclic groups preferably contain 8 to 16 ring atoms.

R_(1a) is preferably hydrogen.

X—X may, for example, be selected from —CH═CH—, —CONR_(1a)—, —NH—CO—,—NH—CH₂—, —CH₂—NH—, —CH₂O—, —OCH₂—, —COO—, —OC═O— and —CH₂CH₂—.

Preferably, the X moiety nearest to the alpha atom is an NH or O atom,most preferably an NH group. The X moiety alpha to the aromatic ring ispreferably a carbon based group such as CH₂ or CO, preferably CO. Thus aparticularly preferred linker X—X is —CONH—.

Examples of particular values for R_(1d) are:

-   hydrogen;-   for (1–6C)alkyl: methyl or ethyl; and-   for phenyl(1–6C)alkyl: benzyl or phenylethyl.

R_(1d) is preferably hydrogen.

Examples of particular values for L are CO, CONH, CON(CH₃) and CONHCH₂,more preferably CO, CONH or CON(CH₃).

It will be appreciated by those skilled in the art that a diverse rangeof organic groups are lipophilic, and that it is therefore impracticalto define with precision each and every structure that may beincorporated into a serine protease inhibitor according to theinvention. Accordingly, it is being assumed that the addressee of thisspecification will not require an exhaustive computer listing ofstructures of lipophilic groups, but will instead make use of thestructures of lipophilic groups disclosed in the specification,especially those exemplified; the test systems described herein foridentifying tryptase inhibitors; and common general knowledge of thelipophilicity, synthesis and stability of organic compounds, to obtainnovel inhibitor compounds of formula (I).

The lipophilic group may be, for example, an alkyl, alkenyl, carbocyclicor heterocyclic group, or a combination of two or more such groupslinked by a spiro linkage or a single or double bond or by C═O, O, OCO,COO, S, SO, SO₂, CONR_(1e), NR_(1e)—CO— or NR_(1e) linkage (where R_(1e)is as defined for R_(1a)), optionally substituted by one or more oxo orR₃ groups in which R₃ is an amino acid residue,N-(1–6C)alkylaminocarbonyl, N,N-di(1–6C)alkylaminocarbonyl,N-(1–6C)alkylaminoalkanoyl, N-(1–6C)alkanoylamino(1–6C)alkanonyl,C-hydroxyamino(1–6C)alkanoyl, hydroxy(2–6C)alkanoylamino(1–6C)alkanoyl,di(1–6C)alkylaminosulfonyl, hydrogen, hydroxyl, (1–6C)alkoxy,(1–6C)alkanoyloxy, (1–6C)alkyl, (2–6C)alkenyl (2–6C)alkynyl,(3–6C)alkenyloxycarbonyl, (1–6C)alkanoyl, amino(1–6C)alkyl,amido(CONH₂), amino(1–6C)alkanoyl, aminocarbonyl(1–5C)alkanoyl,hydroxy(1–6C)alkyl, carboxy, hydroxy(1–6C)alkanoyl,(1–6C)alkoxy(1–6C)alkyl, (1–6C)alkoxycarbonyl(1–5C)alkyl,(1–6C)alkoxycarbonyl, (1–6C)alkanoylamino, amino, halo, cyano, nitro,thiol, (1–6C)alkylthio, (1–6C)alkylsulfonyl, (1–6C)alkylsulphenyl andhydrazido.

Preferably the lipophilic group is a carbocyclic or heterocyclic group,or a combination of a carbocyclic or heterocyclic group with one or morealkyl, alkenyl, carbocyclic or heterocyclic groups, linked by a spirolinkage or a single or double bond or by C═O, O, OCO, COO, S, SO, SO₂,CONR_(1e), NR_(1e)—CO— or NR_(1e) linkage (where R_(1e) is as definedfor R_(1a)), optionally substituted by one or more oxo or R₃ groups.

R_(1e) is preferably a hydrogen atom.

When the lipophilic group comprises an alkyl group, this may be, forexample, a (1–3C)alkyl group, such as methyl, ethyl or propyl.Preferably an alkyl group is unsubstituted.

When the lipophilic group comprises a carbocyclic group, this may be,for example, a non-aromatic or aromatic, mono or polycyclic hydrocarbongroup containing up to 25, more preferably up to 10 carbon atoms. Thecarbocyclic group may thus be, for example, a cycloalkyl,polycycloalkyl, phenyl or naphthyl group, or a cycloalkyl group fusedwith a phenyl group.

Examples of particular values for a cycloalkyl group are (3–6C)cycloalkyl groups, such as cyclopentyl and cyclohexyl. A cycloalkylgroup is preferably unsubstituted or substituted by one group R₃,preferably an amino or alkyl group.

Examples of particular values for a polycycloalkyl group are (6–10C)polycycloalkyl groups, such as bicycloalkyl, for example decalinyl ornorbornyl. A polycycloalkyl group is preferably unsubstituted orsubstituted by one, two or three R₃ groups, for example alkyl such asmethyl. An example of a polycycloalkyl group substituted by alkyl isisopinocampheyl.

A phenyl group is preferably unsubstituted or substituted by one or twoR₃ groups.

A naphthyl group is preferably unsubstituted or substituted by one R₃group.

Examples of a cycloalkyl or cycloalkenyl group fused with a phenyl groupare indanyl and tetrahydronaphthyl. This group is preferablyunsubstituted or substituted by oxo or one or two R₃ groups. Examples ofgroups substituted by oxo are 1-oxoindan-5-yl,1-oxo-1,2,3,4-tetrahydronaphth-7-yl and1-oxo-1,2,3,4-tetrahydro-naphth-6-yl.

When the lipophilic group comprises a heterocyclic group, this may be,for example, a non-aromatic or aromatic, mono or polycyclic groupcontaining one or two oxygen, nitrogen or sulfur atoms in the ringsystem, and in total up to 25, more preferably up to 10 ring systematoms.

Examples of a heterocyclic group when it is a non-aromatic monocyclicgroup are azacycloalkyl groups, such as pyrrolidinyl and piperidinyl;azacycloalkenyl groups, such as pyrrolinyl; diazacycloalkyl groups, suchas piperazinyl; oxacycloalkyl groups, such as tetrahydropyranyl;oxaazacycloalkyl groups, such as morpholino; and thiacycloalkyl groups,such as tetrahydrothiopyranyl. A non-aromatic monocyclic grouppreferably contains 5, 6 or 7 ring atoms and is preferably unsubstitutedor substituted by one group R₃.

Examples of a heterocyclic group when it is a non-aromatic polycyclicgroup are bicyclic groups, such as azacycloalkyl fused with phenyl, forexample dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl andtetrahydroisoquinolinyl; azacycloalkyl fused with cycloalkyl, such asdecahydroisoquinolinyl; and thienyl fused with cycloalkyl, such astetrahydrobenzo[b]thienyl or 4H-cyclopenta(b)thienyl.

Examples of a heterocyclic group when it is an aromatic monocyclic groupare furyl, pyrrolyl, thienyl, imidazolyl, thiazolyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, preferablyunsubstituted or substituted by one or two R₃ groups.

Examples of a heterocyclic group when it is an aromatic polycyclic groupare bicyclic groups such as benzofuryl, quinolinyl, isoquinolinyl,benzothienyl, indolyl and benzothiazolyl.

Where Lp comprises a combination of at least two groups, it preferablycomprises a combination of two or three such groups. The groups arepreferably linked by a single bond, C═O, OCO, COO, O or NR_(1e).

Examples of particular values for R₃ are:

-   for an amino acid residue: N-acetylalaninoyl, serinoyl, threoninoyl,    aspartoyl or glutamoyl;-   for N-(1–6C)alkylaminocarbonyl: N-(1,3-dimethyl)butylamino-carbonyl;-   for N,N-di(1–6C)alkylaminocarbonyl: N-methyl-N-ethylaminocarbonyl;-   for N-(1–6C)alkylaminoalkanoyl: N-methylacetyl;-   for N-(1–6C)alkanoylamino(1–6C)alkanonyl: 2-N-acetylaminoacetyl,    2-N-acetylaminopropanoyl or 2-N-(2-methylpropanoyl)aminoacetyl;-   for C-hydroxyamino(1–6C)alkanoyl: 2-amino-3-hydroxypropanoyl or    2-amino-3-hydroxybutanoyl;-   for hydroxy(2–6C)alkanoylamino(1–6C)alkanoyl:    2-hydroxyacetylaminoacetyl;-   for di(1–6C)alkylaminosulfonyl: dimethylaminosulfonyl; hydrogen;-   hydroxyl;-   for (1–6C)alkoxy: methoxy;-   for (1–6C)alkanoyloxy: acetoxy;-   for (1–6C)alkyl: methyl, ethyl, propyl, 2-propyl or    2,2-dimethylethyl;-   for (2–6C)alkenyl: allyl;-   for (2–6C)alkynyl: propynyl;-   for (3–6C)alkenyloxycarbonyl: allyloxycarbonyl;-   for (1–6C)alkanoyl: acetyl, propionyl or isobutyryl;-   for amino(1–6C)alkyl: aminomethyl;-   amido(CONH₂);-   for amino(1–6C)alkanoyl: aminoacetyl(COCH₂NH₂), aminopropionyl    (COCH₂CH₂NH₂) or 2-aminopropionyl(COCH(CH₃)NH₂);-   for aminocarbonyl(1–5C)alkanoyl: aminocarbonylacetyl;-   for hydroxy(1–6C)alkyl: hydroxymethyl or 1-hydroxyethyl;-   carboxy;-   for hydroxy(1–6C)alkanoyl: 2-hydroxyacetyl or 2-hydroxypropanoyl;-   for (1–6C)alkoxy(1–6C)alkyl: methoxymethyl;-   for (1–6C)alkoxycarbonyl(1–5C)alkyl: methoxycarbonylmethyl;-   for (1–6C)alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl;-   for (1–6C)alkanoylamino: formylamino or acetylamino;-   amino;-   for halo: chloro;-   cyano;-   nitro;-   thiol;-   for (1–6C)alkylthio: methylthio;-   for (1–6C)alkylsulfonyl: methylsulphonyl or ethylsulfonyl;-   for (1–6C)alkylsulphenyl: methylsulphenyl; and-   hydrazido.

Most preferably, the lipophilic group is selected from

wherein R₃ is as hereinbefore defined; and

X represents CH or N.

In the Lp groups depicted above, preferably L represents CO when the Lpgroup is linked to L through N, or CONR_(1d) (such as CONH or CONCH₃)when the Lp group is linked to L through C.

One group of compounds of particular interest is that in which Lrepresents CO and Lp represents

In this group of compounds, R₃ preferably represents hydrogen, hydroxylor (1–6C)alkylaminocarbonyl.

Examples of particular values for Lp in this sub-group arepyrrolidin-1-yl, piperidin-1-yl, N-methyl,N-ethylaminocarbonylpiperidin-1-yl, decahydroisoquinolin-2-yl and2,3-dihydroindol-1-yl.

Another group of compounds of particular interest is that in which Lrepresents CONR_(1d) (such as CONH or CONCH₃) and Lp represents

in which X is CH or N.

In this group of compounds, each R₃ is preferably selected independentlyfrom hydrogen, amino, hydroxy, (1–6C)alkyl, (1–6C)alkanoyl,(1–6C)alkanoyloxy, (1–5C)alkoxycarbonyl(1–6C)alkyl, amino(1–6C)alkyl orcyano.

Thus, values for R₃ in this group include hydrogen, amino, hydroxy,alkyl or aminoalkyl.

Examples of particular values are:

-   (i) 2-aminocyclohexyl;-   (ii) 2-aminobenzothiazol-6-yl;-   (iii) quinolin-3-yl or 8-acetoxyquinolin-2-yl;-   (iv) 4-piperidin-1-ylphenyl or 4-piperazin-1-ylphenyl;-   (v) 1-oxoindan-5-yl;-   (vi) indan-5-yl;-   (vii) tetrahydronaphth-6-yl or 1-methyltetrahydronaphth-6-yl;-   (viii) 1-oxotetrahydronaphth-6-yl or 1-oxotetrahydronaphth-7-yl;-   (ix) 2,3-dimethylindol-5-yl;-   (x) N-benzyl-3-acetylindol-5-yl or N-benzyl-3-acetylindol-7-yl;-   (xi) 3-ethoxycarbonyl-4,5-dimethylthien-2-yl;-   (xii) 4-methyl-5-acetylthiazol-2-yl, 4,5-dimethylthiazol-2-yl,    4-methyl-5-ethoxycarbonylthiazol-2-yl,    3-cyano-4-methyl-5-ethoxycarbonylthiazol-2-yl or    4-methoxycarbonylmethyl-5-methylthiazol-2-yl;-   (xiii) 5-phenylthiazol-2-yl;-   (xiv) 2-methoxycarbonyl-5-(t-butyl)thien-3-yl;-   (xv) 2-acetyl-5-phenylthien-3-yl; and-   (xvi) 5,6-dihydro-3-methoxycarbonyl-4H-cyclopenta(b)thiophen-2-yl.

Another group of compounds of particular interest is that in which Lrepresents CONR_(1d) (such as CONH or CONCH₃) and Lp represents

in which R₃ is (1–6C)alkylaminocarbonyl,N-(1–6C)alkylamino(1–6C)alkanoyl, N-(1–6C)alkanoylamino(1–6C)alkanonyl,C-hydroxyamino(1–6C)alkanoyl, hydrogen, (1–6C)alkoxy, (1–6C)alkyl,amino(1–6C)alkyl, aminocarbonyl, hydroxy(1–6C)alkyl,(1–6C)alkoxy(1–6C)alkyl, (1–6C)alkoxycarbonyl,(1–6C)acyloxymethoxycarbonyl, (1–6C)alkylamino, amino, halo, cyano,nitro, thiol, (1–6C)alkylthio, (1–6C)alkylsulphonyl,(1–6C)alkylsulphenyl, triazolyl, imidazolyl, tetrazolyl, hydrazido,(1–6C)alkylimidazolyl, thiazolyl, (1–6C)alkylthiazolyl,(1–6C)alkyloxazolyl, oxazolyl, (1–6C)alkylsulphonamido,(1–6C)alkylaminosulphonyl, aminosulphonyl, (1–6C)haloalkoxy or(1–6C)haloalkyl.

Preferably the phenyl group is unsubstituted or substituted by one ortwo R₃ groups.

Examples of particular values are phenyl, 3-cyano-4-methylphenyl,3-aminocarbonylphenyl, 4-aminocarbonylphenyl,4-chloro-3-aminocarbonylphenyl, 4-chlorophenyl, 3,5-dichlorophenyl,3-aminomethylphenyl, 4-methyl-3-acetylaminophenyl,4-(1-hydroxethyl)phenyl and 4-isopropylphenyl.

Another particular group of compounds of formula I is that in which Lrepresents CONR_(1d) (such as CONH or CONCH₃) and Lp represents

In this group of compounds, the heterocyclic group is preferablysubstituted by one or two R₃ groups. Each R₃ group is preferablyselected from hydrogen, halogen such as chlorine, (1–6C)alkyl, such asmethyl, and (1–6C)alkoxy, such as methoxy.

Accordingly, examples of particular values for Lp are:benzothiazol-2-yl, 4-chlorobenzothiazol-2-yl,4-methylbenzo-thiazol-2-yl, 6-methylbenzothiazol-2-yl,4-methoxybenzo-thiazol-2-yl and 5,6-dimethylbenzothiazol-2-yl.

Another particular group of compounds of formula I is that in which Lrepresents CONR_(1d) (such as CONH or CONCH₃) and Lp represents

in which R_(3x) represents R₃ or a group of formula—(X_(1y))_(p)-(G₁)-R_(j)in which p is 0 or 1; X_(1y) represents CO, COO, CONH or SO₂; G₁represents (1–3C)alkanediyl, CH₂OCH₂ or, when p is 1, a bond; and R_(j)represents a carbocyclic or heterocyclic group, optionally substitutedby R₃.

Within this group of compounds, a sub-group of compounds may beidentified in which R_(3x) represents R₃ or a group of formula—(CO)_(p)-(G₁)-R_(j)in which p is 0 or 1 and G₁ represents (1–3C)alkanediyl or, when p is 1,a bond.

It will be appreciated that when Lp represents a group as describedabove, it corresponds to a group in which Lp is a combination of aheterocyclic group (2,3-dihydroindolyl), a carbocyclic or heterocyclicgroup (R_(j)) and optionally an alkyl group (G₁), which groups arelinked by a single bond or a carbonyl group. Accordingly, examples ofparticular values for R_(j) are the examples given above for acarbocyclic or heterocyclic group forming part of Lp. Particular mentionmay be made of pyrrolidinyl, such as pyrrolidin-1-yl or pyrrolidin-2-yl;piperidinyl, such as piperidin-3-yl or piperidin-4-yl; aminocycloalkyl,such as 2-aminocyclohexyl or 4-aminocyclohexyl; phenyl; 2-hydroxypheny;3-hydroxphenyl; 4-hydroxyphenyl; 4-aminomethylphenyl;4-acetylaminomethylphenyl; 4-isopropylphenyl; 3,4-dihydroxyphenyl;naphthyl, such as 1-naphthyl; quinolinyl, such as 8-quinolinyl;aminothiazolyl, such as 2-aminothiazol-4-yl; formamidothiazolyl, such as2-formamidothiazol-4-yl; imidazolyl, such as imidazol-4-yl; and pyridyl,such as pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.

Examples of values for G₁ are a bond, —CH₂—, CH₂CH₂ and CH₂OCH₂.

The 2,3-dihydroindolyl group in the above formula is preferably a2,3-dihydroindol-5-yl or -6-yl group, especially a 2,3-dihydroindol-6-ylgroup.

Examples of structures of compounds comprising a 2,3-dihydroindolylgroup as described above are:

When R₃ is a substituent on the 1-position of a 2,3-dihydroindolylgroup, it preferably represents an amino acid residue;(1–6C)alkylaminocarbonyl; N-(1–6C)alkylamino(1–6C)alkanoyl;N-alkanoylaminoalkanonyl; C-hydroxyamino(1-6C)alkanoyl;hydroxy(1–6C)alkanoylamino(1–6C)alkanoyl; di(1–6C)alkylaminosulfonyl;hydrogen; (1–6C)alkyl; (1–6C)alkanoyl; (1–6C)alkoxycarbonyl;(1–6C)acyloxymethoxycarbonyl; amino(1-6C)alkyl; amido(CONH₂);amino(1–6C)alkanoyl; aminocarbonyl(1–6C)alkanoyl; hydroxy(1–6C)alkyl;hydroxy(1–6C)alkanoyl; (1–6C)alkoxy(1–6C)alkyl;(1–6C)alkoxycarbonyl(1–6C)alkyl; (1–6C)alkoxycarbonyl;(1–6C)alkanoylamino; or (1–6C)alkylsulfonyl. Examples of particularvalues are: N-methylaminoacetyl, N-acetylaminoacetyl,N-acetylaminopropanoyl, N-(2-methylpropanoyl)aminoacetyl,N-acetylalaninoyl, serinoyl, threoninoyl, aspartoyl, glutamoyl,2-hydroxyacetylaminoacetyl, dimethylaminosulfonyl, hydrogen, methyl,acetyl, propanoyl, 2-methylpropanoyl, 3-methylbutyryl,2-hydroxypropanoyl, hydroxyacetyl, methoxycarbonylmethyl,methoxycarbonyl, amido, aminoacetyl, aminocarbonylacetyl, alaninoyl,methylsulfonyl or ethylsulfonyl group.

Accordingly, examples of particular values for Lp are:1-(N-methylaminoacetyl)-2,3-dihydroindol-6-yl;1-(N-acetylaminoacetyl)-2,3-dihydroindol-6-yl;1-(N-acetylaminopropanoyl)-2,3-dihydroindol-6-yl;1-N-(2-methylpropanoyl)aminoacetyl)-2,3-dihydroindol-6-yl;1-(N-acetylalaninoyl)-2,3-dihydroindol-6-yl;1-(serinoyl)-2,3-dihydroindol-6-yl;1-(threoninoyl)-2,3-dihydroindol-6-yl;1-(aspartoyl)-2,3-dihydroindol-6-yl;1-(glutamoyl)-2,3-dihydroindol-6-yl;1-(2-hydroxyacetylamino)acetyl-2,3-dihydroindol-6-yl,1-(2-hydroxyacetylamino)acetyl-2,3-dihydroindol-6-yl,1-amido-2,3-dihydroindol-6-yl, 2,3-dihydroindol-5-yl;1-methyl-2,3-dihydroindol-6-yl;1-allyloxycarbonyl-2,3-dihydroindol-5-yl;1-acetyl-2,3-dihydroindol-6-yl; 1-propanoyl-2,3-dihydroindol-6-yl;1-(2-methylpropanoyl)-2,3-dihydroindol-6-yl;1-(3-methylbutyryl)-2,3-dihydroindol-6-yl;1-(2-hydroxpropanoyl)-2,3-dihydroindol-6-yl;1-hydroxacetyl-2,3-dihydroindol-6-yl;1-methoxycarbonylmethyl-2,3-dihydroindol-6-yl;1-methoxycarbonyl-2,3-dihydroindol-6-yl;1-aminoacetyl-2,3-dihydroindol-6-yl;1-aminocarbonylacetyl-2,3-dihydroindol-6-yl;1-alaninoyl-2,3-dihydroindol-6-yl;1-methylsulfonyl-2,3-dihydroindol-6-yl or1-ethylsulfonyl-2,3-dihydroindol-6-yl.

When R₃ is a substituent on a cyclohexyl, phenyl, naphthyl, thiazolyl,imidazolyl, pyridyl or quinolinyl group, it is preferably hydrogen,hydroxy, amino, alkanoylamino, alkyl, aminoalkyl or alkanoylaminoalkyl.Examples of particular values are hydrogen, hydroxy, amino, formylamino,isopropyl, aminomethyl and acetylaminomethyl.

Accordingly, further examples of particular values for Lp are:2,3-dihydroindol-5-yl,1-(2-aminocyclohexyl)-carbonyl-2,3-dihydroindol-6-yl,1-(4-aminocyclohexyl)-acetyl-2,3-dihydroindol-6-yl,1-prolinoyl-2,3-dihydroindol-6-yl,1-pyrrolidin-2-ylacetyl-2,3-dihydroindol-6-yl,1-piperidin-3-ylcarbonyl-2,3-dihydroindol-6-yl,1-piperidin-3-ylacetyl-2,3-dihydroindol-6-yl,1-phenylacetyl-2,3-dihydroindol-6-yl,1-(2-hydroxy)phenylacetyl-2,3-dihydroindol-6-yl,1-(3-hydroxy)phenylacetyl-2,3-dihydroindol-6-yl,1-(4-hydroxy)phenylacetyl-2,3-dihydroindol-6-yl,1-(3,4-dihydroxy)phenylacetyl-2,3-dihydroindol-6-yl,1-(4-aminomethyl)phenylacetyl-2,3-dihydroindol-6-yl,1-(4-acetylaminomethyl)phenylacetyl-2,3-dihydroindol-6-yl,1-(4-isopropyl)phenylacetyl-2,3-dihydroindol-6-yl,1-phenylsulfonyl-2,3-dihydroindol-6-yl,1-benzylsulfonyl-2,3-dihydroindol-6-yl,1-naphth-1-ylsulfonyl-2,3-dihydroindol-6-yl,1-quinolin-8-ylsulfonyl-2,3-dihydroindol-6-yl,1-(4-pyridyl)acetyl-2,3-dihydroindol-6-yl,1-(3-pyridyl)acetyl-2,3-dihydroindol-6-yl,1-imidazol-4-ylacetyl-2,3-dihydroindol-6-yl,1-(2-aminothiazol-4-yl)acetyl-2,3-dihydroindol-6-yl, and1-(2-formamidothiazol-4-yl)acetyl-2,3-dihydroindol-6-yl, and1-benzyl-2,3-dihydroindol-6-yl.

Another particular group of compounds of formula I is that in which Lrepresents CONR_(1d) (such as CONH or CONCH₃) and Lp represents

in which R_(3y) represents R₃ or a group of formulaR_(k)-G₂-X_(a)—in which G₂ represents a bond or (1–3C)alkanediyl, X_(a) represents abond, CO, OCO, COO or NHCO, and R_(k) represents a carbocyclic orheterocyclic group, optionally substituted by R₃.

It will be appreciated that when Lp represents a group as describedabove, it corresponds to a group in which Lp is a combination of aheterocyclic group (tetrahydrobenzothienyl), a carbocyclic orheterocyclic group (R_(k)) and optionally an alkyl group (G₂), whichgroups are linked by a single bond, or a CO, OCO, COO or NHCO group.Accordingly, examples of particular values for R_(k) are the examplesgiven above for a carbocyclic or heterocyclic group forming part of Lp.Particular mention may be made of phenyl; cycloalkyl, such ascyclopropyl; azacycloalkyl, such as piperidi-1-yl; oxazacycloalkyl, suchas morpholino; and pyridyl, such as pyrid-3-yl.

Examples of values for G₂ are a bond, —CH₂—, and CH₂CH₂. Examples ofstructures of compounds comprising a 4,5,6,7-tetrahydrobenzothienylgroup as described above are:

When R₃ is present as a substituent at the 3-position of a4,5,6,7-tetrahydrobenzothiophene group, it preferably represents acarboxy group; a (1–6C)alkoxycarbonyl group, such as methoxycarbonyl orethoxycarbonyl; or a (1–6C)alkylaminocarbonyl group, such asN-1,3-dimethylbutylaminocarbonyl.

Accordingly, examples of particular values for Lp are:3-carboxy-4,5,6,7-tetrahydrobenzothien-2-yl,3-ethoxy-carbonyl-4,5,6,7-tetrahydrobenzothien-2-yl and3-N-(2,3-dimethylbutylaminocarbonyl-4,5,6,7-tetrahydrobenzothien-2-yl.

When R₃ is present as a substituent on a phenyl or pyridyl group, it ispreferably a hydrogen atom.

Accordingly, further examples of particular values for Lp are:3-benzyloxycarbonyl-4,5,6,7-tetrahydrobenzothien-2-yl,3-benzylaminocarbonyl-4,5,6,7-tetrahydrobenzothien-2-yl,3-(3-pyridyl)methylaminocarbonyl-4,5,6,7-tetrahydro-benzothien-2-yl,3-cyclopropylmethylaminocarbonyl-4,5,6,7-tetrahydrobenzothien-2-yl,3-morpholinocarbonyl-4,5,6,7-tetrahydrobenzothien-2-yl and3-piperidinocarbonyl-4,5,6,7-tetrahydrobenzothien-2-yl.

The cyclic group attached to the alpha carbon is preferably cycloalkyl(such as cyclohexyl), piperidinyl (such as piperidin-4-yl), phenyl,3,4-methylenedioxyphenyl, furyl, such as fur-2-yl, thienyl (such asthien-2-yl or thien-3-yl), imidazolyl (such as imidazol-4-yl), thiazolyl(such as thiazol-4-yl or thiazol-5-yl), pyridyl (such as pyrid-2-yl,pyrid-3-yl or pyrid-4-yl), naphthyl (such as naphth-1-yl ornaphth-2-yl), benzofuryl (such as benzofur-2-yl), benzo[b]thienyl (suchas benzo[b]thien-2-yl) group, optionally substituted by R_(3a) orR_(3i)X_(i) in which X_(i) is a bond, O, NH or CH₂ and R_(3i) is phenyloptionally substituted by R_(3a).

In one group of compounds, each R_(3a) independently is hydroxyl,(1–6C)alkoxy, (1–6C)alkyl, (1–6C)alkanoyl, (1–6C)alkylaminoalkyl,hydroxy(1–6C)alkyl, carboxy, (1–6C) alkoxyalkyl, (1–6C)alkoxycarbonyl,(1–6C)alkylaminocarbonyl, amino(1–6C)alkyl CONH₁₂ CH₂CONH₂, aminoacetyl,(1–6C)alkanoylamino, (1–6C)alkoxycarbonylamino, amino, halo, cyano,nitro, thiol, (1–6C)alkylthio, (1–6C)alkylsulphonyl,(1–6C)alkylsulphenyl, imidazolyl, hydrazido, (1–6C)alkylimidazolyl,(1–6C)alkylsulphonamido, (1–6C) alkylaminosulphonyl, aminosulphonyl,(1–6C) haloalkoxy, or (1–6C) haloalkyl.

Examples of particular values for R_(3a) are:

-   hydrogen;-   hydroxyl;-   for (1–6C)alkoxy: methoxy, ethoxy or isopropoxy;-   for (1–6C)alkyl: methyl, ethyl or isopropyl;-   for: (1–6C)alkanoyl: acetyl, propanoyl or isopropanoyl,-   for (1–6C)alkylaminoalkyl: methylaminomethyl or dimethylaminomethyl;-   for (1–6C)hydroxyalkyl: hydroxymethyl carboxy;-   for (1–6C)alkoxyalkyl: methoxymethyl;-   for (1–6C)alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl;-   for (1–6C)alkylaminocarbonyl: methylaminocarbonyl or    dimethylaminocarbonyl;-   for (1–6C)aminoalkyl: aminomethyl;-   CONH₂;-   CH₂CONH₂;-   aminoacetyl;-   for (1–6C)alkanoylamino: formylamino or acetylamino;-   for (1–6C)alkoxycarbonylamino: methoxycarbonylamino,    ethoxycarbonylamino or t-butoxycarbonylamino;-   amino;-   for halo: fluoro or chloro;-   cyano;-   nitro;-   thiol;-   for (1–6C)alkylthio: methylthio;-   for (1–6C)alkylsulphonyl: methylsulphonyl or ethylsulphonyl;-   for (1–6C)alkylsulphenyl: methylsulphenyl;-   for imidazolyl: imidazol-4-yl;-   hydrazido;-   for (1–6C)alkylimidazolyl: 2-methylimidazol-4-yl;-   for (1–6C)alkylsulphonamido: methylsulphonylamido or    ethylsulphonylamido;-   for (1–6C)alkylaminosulphonyl: methylaminosulphonyl or    ethylaminosulphonyl;-   aminosulphonyl;-   for (1–6C) haloalkoxy: trifluoromethoxy; and-   for (1–6C) haloalkyl: trifluoromethyl.

An example of a particular value for R_(3i) is phenyl.

Examples of particular values for R_(3i)X_(i) are phenyl, phenoxy,phenylamino and benzyl.

Cy is preferably unsubstituted or substituted by one or two R_(3a)groups.

Preferably R_(3a) is hydrogen, hydroxyl, methyl, ethyl, isopropyl,acetyl, propanoyl, isopropanoyl, isopropoxy, amino, aminomethyl,hydroxymethyl, carboxy, amido, formylamino, acetylamino, aminoacetyl orcarboxy.

Examples of particular values for Cy are cyclohexyl, piperidin-4-yl,1-acetylpiperidin-4-yl, 1-propanoylpiperidin-4-yl,1-isobutyrylpiperidin-4-yl, 1-aminoacetylpiperidin-4-yl, phenyl,4-aminophenyl, 3-hydroxyphenyl, 4-methylphenyl, 2,4-dimethylphenyl,3,6-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-hydroxphenyl,3-aminomethylphenyl, 4-aminomethylphenyl, 4-(H₂NCO)phenyl,4-hydroxymethylphenyl, 3-hydroxymethylphenyl, 2-hydroxymethylphenyl,4-carboxyphenyl, 4-isopropoxyphenyl, 2-chlorophenyl,3,4-methylenedioxyphenyl, 4-phenylphenyl, 4-phenoxyphenyl,5-methylfur-2-yl, imidazol-4-yl, 2-methylthiazol-4-yl,2-aminothiazol-4-yl, 2-formylaminothiazol-4-yl, 2-aminothiazol-5-yl,2-formylaminothiazol-5-yl, 2-phenylthiazol-4-yl, 4-aminopyrid-3-yl,6-methylpyrid-2-yl, 3-amino-pyrid-4-yl, naphth-1-yl, naphth-2-yl,benzofur-2-yl or 3-methylbenzothien-2-yl.

A group of compounds of particular interest is that in which Cy is agroup of formula

In which one of X^(a) and X^(b) is N and the other is NH or S, and eachof R_(3r) and R_(3a) is as defined for R_(3a).

Another group of compounds of particular interest is that of formula

in which:

L-Lp represents CO-L_(x); and

L_(x) is a mono or bicyclic group bound to the carbonyl via a pendentnitrogen atom or nitrogen atom which forms part of the mono or bicyclicring;

or a physiologically tolerable salt thereof, e.g. a halide, phosphate orsulphate salt or a salt with ammonium or an organic amine such asethylamine or meglumine.

It will be appreciated that when L_(x) is bound to the carbonyl via apendant nitrogen, the group CO-L_(x) corresponds with the group L-Lp inwhich L is CONH and Lp is a mono or bicyclic group. When Lx is bound tothe carbonyl via a nitrogen that forms part of the mono or bicyclicring, the group CO-Lx corresponds with the group L-Lp in which L is COand Lp is a mono or bicyclic group containing a nitrogen atom in thering and bound to L via this nitrogen.

It is believed that an aminomethyl group positioned on the 3 position ofthe phenyl ring will give rise to excellent binding within the S1binding pocket of tryptase. Without wishing to be limited by theory itis believed that the presence of a hydrogen bond donating group attachedto the phenyl group will be essential for successful inhibition oftryptase.

R₅ and R₆ are both preferably hydrogen.

Most preferably the Lx group comprises

wherein:

A and B are independently chosen from NH, N, O, S, CH, CH₂;

X_(1x) and X_(2x) are independently chosen from (CH₂)_(m),(CH₂)_(m)CH═CH(CH₂)_(p), CO(CH₂)_(m), NH(CH₂)_(m), NHCO(CH₂)_(m),CONH(CH₂)_(m), SO₂NH(CH₂)_(m), NHSO₂ (CH₂)_(m);

n is 1 or 2;

m is 0 to 2;

p is 0 to 2;

R_(1x) and R_(2x) are independently chosen from hydrogen, alkoxy, alkyl,aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, amino, halo,cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, oxo,heterocyclo optionally substituted by R_(3x), cycloalkyl optionallysubstituted by R_(3x) or aryl optionally substituted by R_(3x); and

R_(3x) is hydrogen, alkoxy, alkyl, amino, hydroxy, alkoxy,alkoxycarbonyl, halo, cyano, nitro, thiol, sulphonyl, or sulphenyl.

Examples of heterocyclic R_(1x) and R_(2x) groups are piperidine,piperazine and pyrrolidine.

The cyclic group attached to the alpha atom is preferably an optionallyR_(3a) substituted phenyl.

Thus, one group compounds of the invention are those of formula (II)

wherein Lx is as hereinbefore defined. It is envisaged that especiallypreferred Lx groups will be those in which a cyclic or bicyclic ring issubstituted by hydrogen bond donating and/or acceptor groups.

The compounds of the invention may be prepared by conventional chemicalsynthetic routes, e.g. by amide bond formation to couple the aromaticfunction to the alpha atom and to couple the lipophilic function to thealpha atom. The cyclic group-alpha atom combination may convenientlyderive from an alpha amino acid (preferably of D configuration) with thearomatic deriving from for example an acid derivative of a compoundbased on R₂, e.g. an aminomethylbenzoic acid (which is readilyavailable). Amide formation from such reagents (in which any amino orhydroxyl function (especially in an aminomethyl group) may if desired beprotected during some or all of the synthesis steps) yields a compoundof formula (V).R₂—CONH—CH(Cy)-COOH  (V)(where R₂ represents

and Cy is as defined above).

Prior to reaction the amino group in an aminoalkyl group should beprotected by an appropriate protecting group, PG, e.g. Boc, Z, Fmoc orBpoc. The use of protecting groups is described in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum, 1973 and Greene, “ProtectiveGroups in Organic Synthesis”, Wiley Interscience, 1981.

The lipophilic group may then conveniently be introduced by reaction ofa compound of formula (V) (or another analogous carboxylic acid)optionally after transformation into an activated form, e.g. an acidchloride or active ester, with a lipophilic group carrying or containingan amine group to produce a compound with the linkage of —CO— or—CO—NR_(1d)(CH₂)_(m)— from the alpha atom to the lipophilic group. Theprotecting group, PG, is then removed.

Alternatively a compound of formula V or another analogous carboxylicacid may be transformed into an alcohol by reaction withisobutylchloroformate and reduction with sodium borohydride.

Such an alcohol, e.g. of formula (VI)R₂—CONH—CH(Cy)CH₂OH  (VI)can be reacted to introduce the lipophilic group by reactions such as:

oxidation of the alcohol to form a corresponding aldehyde (e.g. byoxidation with manganese dioxide or DMSO/oxalyl chloride or DMSO/SO₃ orDess-Martin reagent) which may be reacted to introduce the lipophilicgroup by reactions such as:

reaction with an organometallic, eg a Grignard reagent, optionallyfollowed by oxidation of the resulting hydroxyl group (e.g. with MnO₂,DMSO/oxalyl chloride or Dess-Martin reagent.

In this way compounds with the linkage of —CO— between the alpha carbonand the lipophilic group may be produced.

An alternative route to these compounds is to carry out any of the abovechemical reactions to incorporate the lipophilic group into a protectedintermediate such as a compound of formula (VII).

The protecting group may then be removed before coupling of the3-aminomethylbenzoic acid (optionally protected).

The protection of amino and carboxylic acid groups is described inMcOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973,and Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd. Ed.,John Wiley & Sons, NY, 1991. Examples of carboxy protecting groupsinclude C₁–C₆ alkyl groups such as methyl, ethyl, t-butyl and t-amyl;aryl(C₁–C₄)alkyl groups such as benzyl, 4-nitrobenzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl,2,4,6-trimethylbenzyl, benzhydryl and trityl; silyl groups such astrimethylsilyl and t-butyldimethylsilyl; and allyl groups such as allyland 1-(trimethylsilylmethyl)prop-1-en-3-yl.

Examples of amine protecting groups (PG) include acyl groups, such asgroups of formula RCO in which R represents C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, phenyl C₁₋₆ alkyl, phenyl, C₁₋₆ alkoxy, phenyl C₁₋₆ alkoxy,or a C₃₋₁₀ cycloalkoxy, wherein a phenyl group may be optionallysubstituted, for example by one or two of halogen, C₁–C₄ alkyl and C₁–C₄alkoxy. Preferred amino protecting groups include t-butoxycarbonyl (Boc)and benzyl.

α-Amino acids of formula (VII) which are not commercially available canbe synthesized by methods known in the art, for example as described in“Synthesis of Optically Active α-Amino Acids” by Robert M. Williams(Pergamon Press, 1989) and “Asymmetric Synthesis of ArylGlycines”, Chem.Rev. 1992, 889–917.

Compounds of the type (VII) made be prepared (for example) by one ormore of the following methods.

-   (i) from aryl or heteroaryl aldehydes via the Strecker synthesis or    modifications thereof, via Bucherer-Bergs hydantoin synthesis, or    via the Ugi methodology (Isonitrile Chemistry, Ugi I. Ed.; Academic:    New York, 1971; pp 145–199) with removal and replacement of    protecting groups;-   (ii) from styrenes via Sharpless methodology (J. Am. Chem. Soc.    1998, 120, 1207–1217)-   (iii) from aryl boronic acids via Petasis methodology (Tetrahedron,    1997, 53, 16463–16470) with removal and replacement of protecting    groups;-   (iv) from aryl and heteroaryl acetic acids—via Evan's azidation    (Synthesis, 1997, 536–540) or by oximation, followed by reduction    and addition of protecting groups;-   (v) from existing aryl glycines by manipulation of functional    groups, for example, alkylation of hydroxy groups, palladium    assisted carbonylation of triflates derived from hydroxy groups and    further manipulation of the carboxylic esters to give carboxylic    acids by hydrolysis, carboxamides by activation of the carboxylic    acid and coupling with amines, amines via Curtius reaction on the    carboxylic acid; or-   (vi) from aliphatic, carbocylic and non-aromatic heterocyclic    aldehydes and ketones using a Horner-Emmons reaction with    N-benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (Synthesis,    1992, 487–490).

Examples of synthetic schemes are shown below:

Synthesis of Protected 4-aminomethylphenylgylcine

Synthesis of Protected 4-piperidylglycine

Synthesis of protected 2-aminothiaz-4-ylglycine

Synthesis of Thiazole Lp Groups

Synthesis of Alternative Thiazole Lp Groups Benzthiazole Synthesis fromAnllines

Cyclic Aliphatic Fused Aminothiazoles

Synthesis of Thiophene Lp Groups

Synthesis of Compounds with Different Cyclic Groups (Cy)

Synthesis of Thiazole Cy Groups

Thus viewed from a further aspect, the invention provides a process forthe preparation of a compound according to the invention which processcomprises coupling a lipophilic group to a compound of formula (VIII)R₂—(X)₂—Y(Cy)-Z₁  (VIII)or a protected derivative thereof (wherein R₂, X, Y and Cy are asdefined above and Z₁ is a reactive functional group).

Instead of introducing the group L-Lp as the final stage process step,the compounds of formula I may alternatively be prepared by a process inwhich the group R₂ is introduced in the final process step.

Thus viewed from another aspect the invention provides a process for thepreparation of a compound according to the invention which processcomprises reacting a compound of formula (IX)Z₂-Y(Cy)-L-Lp  (IX)(wherein Y, Cy, L and Lp are as defined above and Z₂ is HX or a reactivefunctional group), or a protected derivative thereof, with a compound offormula (X)R₂-Z₃  (X)(wherein R₂ is as defined above and Z₃ is XH or an appropriate reactivegroup), or a protected derivative thereof, followed if necessary by theremoval of any protecting groups.

Thus, for a compound of formula I in which X—X represents CONH, acompound of formula (IX) in which Z₂ is H₂N may be reacted with acompounds of formula (X) in which Z₃ is COOH or a reactive derivativethereof, such as an acyl halide or an anhydride, for example asdescribed in the Examples herein.

In another aspect the invention relates to a process for preparing acompound of formula I comprising deprotecting a compound of formula(I′):R²′—X—X—Y(Cy′)-L-Lp  (I)′Wherein R²′ is R² (as hereinabove defined) or protected R², Cy′ is Cy(as hereinabove defined) or protected Cy and Lp′ is Lp (as hereinabovedefined) or protected Lp; providing at least one protecting group ispresent.

If necessary physiologically tolerable salts can be formed using methodsknown in the art.

Where the lipophilic group Lp comprises more than one group, it maygenerally be formed by coupling these groups together at an appropriatestage in the preparation of the compound of formula I using conventionalmethods or as described in the Examples.

The compounds of the invention may be administered by any convenientroute, e.g. into the gastrointestinal tract (e.g. rectally or orally),the nose, lungs, musculature or vasculature or transdermally. Thecompounds may be administered in any convenient administrative form,e.g. tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulkingagents, and further active agents. Preferably the compositions will besterile and in a solution or suspension form suitable for injection orinfusion. Such compositions form a further aspect of the invention.

The following are examples of pharmaceutical compositions of compoundsaccording to the invention.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate 10 Total 460 mg

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities.

Formulation 2

Tablets each containing 60 mg of active ingredient are made as follows:

Active Ingredient 60 mg Starch 45 mg Microcrystalline cellulose 35 mgPolyvinylpyrrolidone 4 mg Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1 mg Total 150 mg

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg.

Viewed from this aspect the invention provides a pharmaceuticalcomposition comprising a serine protease (tryptase) inhibitor accordingto the invention together with at least one pharmaceutically acceptablecarrier or excipient.

The pharmaceutical composition may also optionally comprise at least onefurther anti-inflammatory.

Viewed from a further aspect the invention provides the use of atryptase inhibitor according to the invention for the manufacture of amedicament for use in a method of treatment of the human or non-humananimal body (e.g. a mammalian, avian or reptilian body) to combat (i.e.treat or prevent) a condition responsive to said inhibitor.

Viewed from a further aspect the invention provides a method oftreatment of the human or non-human animal body (e.g. a mammalian, avianor reptilian body) to combat a condition responsive to a tryptaseinhibitor.

The dosage of the inhibitor compound of the invention will depend uponthe nature and severity of the condition being treated, theadministration route and the size and species of the patient. However ingeneral, quantities of from 0.01 to 100 μmol/kg bodyweight will beadministered.

All publications referred to herein are hereby incorporated byreference.

The invention will now be described further with reference to thefollowing non-limiting Examples.

EXPERIMENTAL

Abbreviations used follow IUPAC-IUB nomenclature. Additionalabbreviations are HPLC, high-performance liquid chromatography; LC/MS,liquid chromatography/mass spectrometry; rt, retention time; NMR,nuclear magnetic resonance, TBTU,2-(1H-(benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate.Starting materials were purchased from Aldrich (Gillingham, UK),Lancaster (Morecambe, UK), Avocado (Heysham, UK), Maybridge (Tintagel,UK), Nova Biochem (Nottingham, UK) or Bachem.

Purification:

Flash column chromatography was carried out using Merck silica gel Si60(40–63 μm, 230–400 mesh). Purification of final products was bycrystallisation, flash column chromatography or gradient reverse phaseHPLC on a Waters Deltaprep 4000 at a flow rate of 50 mL/minute using aDeltapak C18 radial compression column (40 mm×210 mm, 10–15 mm particlesize). Eluant A consisted of aqueous trifluoroacetic acid (0.1%) andeluant B 90% acetonitrile in aqueous trifluoroacetic acid (0.1%) withgradient elution (Gradient, 0 minutes 5% B for 1 minutes, then 5% B to20% B over 4 minutes, then 20% B to 60% B over 32 minutes). Fractionswere analysed by analytical HPLC and LC/MS before pooling thosewith >95% purity for lyophilisation.

Analysis:

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on aBruker DPX300 (300 MHz). Analytical HPLC's were performed on a ShimadzuLC6 gradient system equipped with an autosampler. Eluant A consisted ofaqueous trifluoroacetic acid (0.1%) and eluant B consisted of 90%acetonitrile and 10% water, containing trifluoroacetic acid (0.1%).Gradient 1 elution began at 5% B and increased to 100% B over sevenminutes. Gradient 2 elution began at 5% B and increased to 100% B overten minutes. Gradient 3 elution began at 5% B for one minute, increasingto 20% B after the fourth minute, 40% B after the 14^(th) minute andthen 100% B after the 15^(th) minute. The columns used were Luna 2 C18(3μ, 30 mm×4.6 mm), Luna 2 C18 (5μ, 150 mm×2 mm) and a Symmetry Rp8(3.5μ, 50×2.1 mm).

LC/MS were performed on a PESCIEX single quadrupole API-150EXinstrument, equipped with a Luna 2 C18 column (3μ, 30 mm×4.6 mm) elutingwith 20% to 100% acetonitrile in water over five minutes.

Example 1 3-(Aminomethyl)benzoyl-D-phenylglycine2-aminobenzothiazol-6-amide bis(trifluoroacetate) salt2,6-Diaminobenzothiazole

2-Amino-6-nitrobenzothiazole (500 mg, 2.56 mmol) was dissolved inmethanol (20 mL) and 10% palladium on carbon (50 mg) was added as aslurry in methanol (1 mL). The atmosphere was replaced with hydrogen andthe suspension was stirred overnight. The catalyst was removed bysuction filtration and the solvent evaporated to afford2,6-diaminobenzothiazole (420 mg, 99%) as a pale yellow solid.

N-BOC-D-Phenylglycine 2-aminobenzothiazol-6-amide

N-BOC-D-Phenylglycine (250 mg, 1.0 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1.0mmol) and 7-aza-1-hydroxybenzotriazole (140 mg, 1.0 mmol) were stirredin dimethylformamide (3 mL) for ten minutes. 2,6-Diaminobenzothiazole(160 mg, 1.0 mmol) was then added and the solution was stirred overnightat room temperature. Ethyl acetate (15 mL) was added and the solutionwas washed with water (5 mL), saturated citric acid solution (5 mL),saturated NaHCO₃ (5 mL) and water (5 mL), and dried over MgSO₄. Thesolvent was removed under reduced pressure to affordN-BOC-D-phenylglycine 2-aminobenzothiazol-6-amide.

¹H NMR (CDCl₃): 8.93 (1H, br s, C(O)NHAr); 7.72 (1H, s, benzothiazoleC(7)H); 7.35 (2H, br s, Ph); 7.23–7.05 (3H, m, Ph); 6.93 (1H, d, J=10Hz, benzothiazole C(4)H or C(5)H); 6.72 (1H, d, J=10 Hz, benzothiazoleC(4)H or C(5)H); 6.05 (1H, d, J=7 Hz, CHPh); 5.92 (2H, br s, NH₂); 5.45(1H, br s, BOCNH); 1.27 (9H, s, ^(t)Bu).

D-Phenylglycine 2-aminobenzothiazol-6-amide

A solution of N-BOC-D-phenylglycine 2-aminobenzothiazol-5amide indichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) andstirred for 30 minutes. The dichloromethane and excess trifluoroaceticacid were removed under reduced pressure and the residue was trituratedwith diethyl ether to afford D-phenylglycine 2-aminobenzothiazol-6-amideas its trifluoroacetate salt (350 mg, 89%).

3-(Aminomethyl)benzoyl-D-phenylglycine 2-aminobenzothiazol-6-amidetrifluoroacetate salt

N-BOC-3-aminomethylbenzoic acid (250 mg, 1.0 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1.0mmol) and 7-aza-1-hydroxybenzotriazole (140 mg, 1.0 mmol) were stirredin dimethylformamide (10 mL) for five minutes. D-Phenylglycine2-aminobenzothiazol-6-amide trifluoroacetate salt (350 mg, 0.85 mmol)was then added and the mixture was stirred overnight. The solution waspoured into ethyl acetate (20 mL) and washed with 5% HCl (5 mL),saturated NaHCO₃ (5 mL) and water (5 mL), dried over MgSO₄ and thesolvent removed under reduced pressure. The crude product was purifiedby flash column chromatography on silica gel (60% ethyl acetate/40%hexane to 100% ethyl acetate) to affordN-BOC-3-(aminomethyl)benzoyl-D-phenylglycine2-aminobenzothiazol-6-amide. This was dissolved in dichloromethane (5mL) and trifluoroacetic acid (5 mL) was added. The solution was stirredat room temperature for 30 minutes before the dichloromethane and excesstrifluoroacetic acid were removed under reduced pressure. The residuewas triturated with diethyl ether to afford3-(aminomethyl)benzoyl-D-phenylglycine 2-aminobenzothiazol-6-amide asits trifluoroacetate salt (150 mg, 32%).

¹H NMR (d₄ MeOH): 8.21 ppm (1H, s, benzothiazole C(7)H); 7.97 (1H, s,aminomethylbenzoyl C(2)H); 7.94 (1H, d, J=5 Hz, 3-(aminomethyl)benzoylC(6)H); 7.80–7.48 (5H, m, Ar); 7.47–7.32 (4H, m, Ar); 5.81 (1H, s,CHPh); 4.22 (2H, s, CH₂NH₂).

HPLC (Luna 2, Gradient 1): rt=2.80 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.40 minutes, 432 (MH)⁺.

Examples 2–34 were prepared in the same fashion as Example 1, startingwith the indicated nitro-compound or amine. Other functional groupspresent were protected appropriately.

Example 2 3-(Aminomethyl)benzoyl-D-phenylglycine phenylamidetrifluoroacetate salt

Prepared from aniline.

¹H NMR (d₄ MeOH): 7.85 ppm (2H, br s, Ar); 7.49 (6H, m, Ar); 7.27 (5H,m, Ar) 7.01 (1H, t, J=9 Hz, Ar); 5.70 (1H, s, CHPh); 4.12 (2H, s,CH₂NH₂).

HPLC (Luna 2, Gradient 1): rt=3.59 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.99 minutes, 360 (MH)⁺.

Example 3 2-Amino-5-(aminomethyl)benzoyl-D-phenylglycine (1S, 2S, 3S,5R)-isopinocamphamide dihydrochloride salt

Prepared from (1S, 2S, 3S, 5R)-(+)-isopinocampheylamine.

¹H NMR (d4 MeOH): 7.52 ppm (1H, s, Ar—C(6)H); 7.42 (2H, d, J=10,2×Ph-o-CH); 7.32–7.2 (3H, m, 2×Ph-m-CH, Ph-p-CH); 7.12 (1H, d, J=11 Hz,Ar—C(4)H); 6.67 (1H, d, J=11 Hz, Ar—C(3)H); 5.53 (1H, s, NCH(Ph)); 4.18(1H, quintet, J=8 Hz, ipc-C(1)H); 3.90 (2H, s, CH ₂NH₂); 2.42–2.23 (2H,m, ipc-C(3)H and ipc-(C(2)H); 1.91 (1H, m, ipc-(C)₆H); 1.80 (1H, br s,ipc-(C)₅H); 1.74 (1H, t, J=5 Hz, ipc-(C)₆H); 1.32 (1H, dd, J=14, 8 Hz,ipc-C(7)H); 1.14 (3H, s, ipc-C(8)H₃); 1.02 (3H, d, J=8 Hz, ipc-C(10)H₃);0.95 (3H, s, ipc-C(9)H₃); 0.87 (1H, d, J=11 Hz, ipc-C(7)H).

HPLC (Luna 2, Gradient 1): rt=4.21 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.10 minutes, 418 (MH-NH₃)⁺.

Example 4 3-(Aminomethyl)benzoyl-D-phenylglycine quinolin-3ylamidetrifluoroacetate salt

Prepared from 3-aminoquinoline.

¹H NMR (d₄ MeOH): 9.21 and 8.88 ppm (1H each, s, quinoline C(2)H andC(4)H); 8.10–7.90 (4H, m, Ar); 7.81 (1H, t, J=7 Hz, Ar); 7.77–7.55 (5H,m, Ar); 7.53–7.25 (3H, m, Ar); 5.91 (1H, s, CHPh); 4.20 (2H, s, CH₂NH₂).

HPLC (Luna 2, Gradient 1): rt=2.98 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 411 (MH)⁺.

Example 5 3-(Aminomethyl)benzoyl-D-phenylglycine4-(1-piperidyl)phenylamide trifluoroacetate salt

Prepared from 4-(1-piperidyl)aniline.

¹H NMR (d₄ MeOH): 7.97 ppm (2H, m, Ar); 7.8 (2H, d, J=9 Hz, Ar);7.7–7.35 (9H, m, Ar); 5.8 (1H, s, CHPh); 4.2 (2H, s, CH₂NH₂); 3.55 (4H,m, pip); 2.0 (4H, m, pip); 1.8 (2H, m. pip).

HPLC (Luna 2, Gradient 1): rt=2.81 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 443 (MH)^(+.)

Example 6 3-(Aminomethyl)benzoyl-D-phenylglycine 1-oxoindan-5-amidetrifluoroacetate salt

Prepared from 5-amino-1-oxoindane.

¹H NMR (d₄ MeOH): 7.98 ppm (1H, s, (aminomethyl)benzoyl C(2)H); 7.96 ppm(1H, d, J=10 Hz, (aminomethyl)benzoyl C(6)H); 7.94 (1H, s, indanoneC(4)H); 7.70–7.52 (6H, m, Ar); 7.47–7.33 (3H, m, Ar); 5.84 (1H, s,CHPh); 4.22 (2H, s, CH₂NH₂); 3.12 (2H, t, J=5 Hz, indanone C(3)H₂);2.82–2.75 (2H, m, indanone C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=3.35 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.78 minutes, 414 (MH)⁺.

Example 7 3-(Aminomethyl)benzoyl-D-phenylglycine3-cyano-4-methylphenyl-amide trifluoroacetate salt

Prepared from 3-cyano-4-methylaniline.

¹H NMR (d₄ MeOH): 8.01 ppm (1H, s, 3-cyano-4-methylphenyl C(2)H); 7.98(1, s, 3-(aminomethyl)benzoyl C(2)H); 7.94 (1H, d, J=9 Hz,3-(aminomethyl)benzoyl C(6)H); 7.72–7.52 (5H, m, Ar); 7.48–7.28 (4H, m,Ar); 5.82 (1H, s, CHPh); 4.19 (2H, s, CH₂NH₂); 2.47 (3H, s, CH₃).

HPLC (Luna 2, Gradient 1): rt=3.72 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 399 (MH)⁺.

Example 8 3-(Aminomethyl)benzoyl-D-phenylglycine 4-amido phenylamidetrifluoroacetate salt

Prepared from 4-nitrobenzamide.

¹H NMR (d₄ MeOH): 8.20–8.05 ppm (2H, m, 3-(aminomethyl)benzoyl C(2)H andC(6)H); 7.97 (2H, d, J=9 Hz, 4-(amidocarbonyl)phenyl C(2)H and C(6)H);7.86 (2H, d, J=9 Hz, 4-(amidocarbonyl)phenyl C(3)H and C(5)H); 7.82–7.65(4H, m, Ar); 7.63–7.47 (3H, m, Ar); 6.01, (1H, s, CHPh); 4.32 (2H, br s,CH₂NH₂).

HPLC (Symmetry C8, Gradient 2): rt=4.84 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.51 minutes, 403 (MH)⁺.

Example 9 3-(Aminomethyl)benzoyl-D-phenylglycine 3-amidophenylamidetrifluoroacetate salt

Prepared from 3-nitrobenzamide.

¹H NMR (d₄ MeOH): 8.30 ppm (1, s, 3-(amidocarbonyl)phenyl C(2)H); 8.17(1H, s, 3-(aminomethyl)benzoyl C(2)H); 8.12 (1H, d, J=8 Hz,3-(aminomethyl)benzoyl C(6)H); 7.93 (1H, d, J=7 Hz,3-(amidocarbonyl)phenyl C(6)H); 7.85–7.68 (5H, m, Ar); 7.65–7.52 (4H, m,Ar); 6.03 (1H, s, CHPh); 4.37 (2H, br s, CH₂NH₂).

HPLC (Luna 2, Gradient 1): rt=2.95 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.78 minutes, 403 (MH)⁺.

Example 10 3-(Aminomethyl)benzoyl-D-phenylglycine1,2,3,4-tetrahydro-1-oxonaphthyl-6-amide trifluoroacetate salt

Prepared from 6-amino-1,2,3,4-tetrahydro-1-oxonaphthalene.

¹H NMR (d₄ MeOH): 7.72 ppm (3H, m, Ar); 7.40 (6H, m, Ar); 7.20 (3H, m,Ar); 5.65 (1H, s, CHPh); 4.02 (2H, s, CH ₂NH₂); 2.78 (2H, t, J=6 Hz,tetrahydronaphthyl C(4)H₂); 2.42 (2H, t, J=7 Hz, tetrahydronaphthylC(2)H₂); 1.95 (2H, m, tetrahydronaphthyl C(3)H₂).

HPLC (Luna 2, gradient 1): rt=3.57 minutes.

LC/MS (Luna 2, gradient 4): rt=1.88 minutes; 428 (MH)⁺.

Example 11 3-(Aminomethyl)benzoyl-D-phenylglycine1,2,3,4-tetrahydro-1-oxonaphthyl-7-amide trifluoroacetate salt

Prepared from 7-nitro-1,2,3,4-tetrahydro-1-oxonaphthalene.

¹H NMR (d₄ MeOH): 8.04 ppm (1H, s, tetrahydronaphthyl C(8)H); 7.82 (2H,dd, J=1, 10 Hz, Ar); 7.60 (2H, dd, Ar); 7.45 (4H, m, Ar); 7.28 (3H, m,Ar); 7.16 (1H, m, Ar); 5.68 (1H, br s, CHPh); 4.03 (2H, s, CH ₂NH₂),2.83 (2H, t, J=7 Hz, tetrahydronaphthyl C(4)H₂); 2.40 (2H, t, J=7 Hz,tetrahydronaphthyl C(2)H₂); 2.00 (2H, m, tetrahydronaphthyl C(3)H₂).

HPLC (Luna 2, gradient 1): rt=3.65 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.94 minutes, 428 (MH)⁺.

Example 12 3-(Aminomethyl)benzoyl-D-phenylglycine1,2,3,4-tetrahydro-naphthyl-6-amide trifluoroacetate salt

Prepared from 6-amino-1,2,3,4-tetrahydronaphthalene.

¹H NMR (d₄ MeOH): 7.72 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 7.70(1H, d, J=7 Hz, 3-(aminomethyl)benzoyl C(6)H); 7.40 (4H, m, Ar); 7.22(3H, m, Ar); 7.09 (1H, m, Ar); 6.82 (1H, m, Ar); 5.62 (1H, s, CHPh);4.00 (2H, s, CH ₂NH₂); 2.50 (4H, s,); 1.58 (4H, s, tetrahydronaphthylC(4)H₂ and C(5)H₂).

HPLC (Luna 2, Gradient 4): rt=4.21 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.21 minutes, 414 (MH)⁺.

Example 13 3-(Aminomethyl)benzoyl-D-phenylglycine4-(piperazin-1-yl)phenyl-amide bis(trifluoroacetate) salt

Prepared from 4-(piperazin-1-yl)aniline.

¹H NMR (d₄ MeOH): 8.00 ppm (2H, m, Ar); 7.70–7.35 (9H, m, Ar); 7.02 (2H,d, J=10 Hz, Ar); 5.80 (1H, s, CHPh); 4.21 (2H, s, CH₂NH₂); 3.30 (8H, m,pip).

HPLC (Luna 2, Gradient 1): rt=2.71 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 444 (MH)⁺.

Example 14 3-(Aminomethyl)benzoyl-D-phenylglycine 2,3-dihydroindol5-amide bis(trifluoroacetate) salt

Prepared from 2,3-dihydro-5-nitroindole.

¹H NMR (d₄ MeOH): 7.97 ppm (2H, m, Ar); 7.82 (1H, s, Ar); 7.65 (5H, m,Ar); 7.45 (4H, m, Ar); 5.80 (1H, s, CHPh); 4.20 (2H, s, CH ₂NH₂); 3.85(2H, t, J=7.5 Hz, dihydroindole C(2)H ₂); 3.30 (2H, t, J=7.5 Hz,dihydroindole C(3)H ₂).

HPLC (Luna 2, Gradient 1): rt=2.59 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 401 (MH)⁺.

Example 15 3-(Aminomethyl)benzoyl-D-phenylglycine4-chloro-3-amidophenylamide trifluoroacetate salt

Prepared from 2-chloro-5-nitrobenzamide.

¹H NMR (d₄ MeOH): 7.98 ppm (1, s, 3-(aminomethyl)benzoyl C(2)H); 7.94(1H, d, J=9 Hz, 3-(aminomethyl)benzoyl C(6)H); 7.83 (1H, s,2-chloro-3-(amidocarbonyl)-phenyl C(6)H); 7.70–7.50 (5H, m, Ar);7.45–7.35 (4H, m, Ar); 5.58 (1H, s, CHPh); 4.21 (2H, s, CH ₂NH₂).

HPLC (Luna 2, Gradient 1): rt=3.09 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.62 minutes, 437/439 (MH)⁺.

Example 16 3-(Aminomethyl)benzoyl-D-phenylglycine3,5-dichlorophenylamide trifluoroacetate salt

Prepared from 3,5-dichloroaniline.

¹H NMR (d₄ MeOH): 7.98 ppm (1, s, 3-(aminomethyl)benzoyl C(2)H); 7.94(1H, d, J=9 Hz, 3-(aminomethyl)benzoyl C(6)H); 7.73–7.51 (4H, m, Ar);7.64 (2H, s, 3,5-dichlorophenyl C(2)H and C(6)H); 7.49–7.32 (3H, m, Ar);7.18 (1H, s, 3,5-dichlorophenyl C(4)H); 5.80 (1H, s, CHPh); 4.20 (2H, s,CH₂NH₂).

HPLC (Luna 2, Gradient 1): rt=4.31 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.29 minutes, 428/430/432 (MH)⁺.

Example 17 3-(Aminomethyl)benzoyl-D-phenylglycine3-(aminomethyl)phenyl-amide bis(trifluoroacetate) salt

Prepared from 3-nitrobenzylamine.

¹H NMR (d₄ MeOH): 7.97 ppm (2H, m Ar); 7.82 (1H, s, Ar); 7.61 (5H, m,Ar); 7.40 (4H, m, Ar); 7.22 (1H, d, J=11 Hz, Ar); 5.81 (1H, s, CHPh);4.22 (2H, s, CH ₂NH₂); 4.10 (2H, s, CH ₂NH₂).

HPLC (Luna 2, Gradient 1): rt=2.67 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 389 (MH)⁺.

Example 18 3-(Aminomethyl)benzoyl-D-phenylglycine2,3-dimethylindol-5-amide bis(trifluoroacetate) salt

Prepared from 2,3-dimethyl-5-nitroindole.

¹H NMR (d₃ acetonitrile): 9.12 ppm (1H, br s, NH); 9.08 (1H, bs, NH);8.40 (1H, d, J=7 Hz, Ar), 8.20 (1H, s, Ar); 8.0 (1H, d, J=7 Hz, Ar);7.88–7.50 (7H, m, Ar); 7.30 (2H, m, Ar); 6.0 (1H, d, J=6.5 Hz, CHPh);4.30 (2H, s, CH ₂NH₂); 2.71 (2H, br s, CH₂NH ₂); 2.50 (3H, s, indoleC(3)CH ₃); 2.31 (3H, s, indole C(2)CH ₃).

HPLC (Luna 2, Gradient 1): rt=3.76 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.99 minutes, 427 (MH)⁺.

Example 19 3-(Aminomethyl)benzoyl-D-phenylglycine 4-chlorophenylamidetrifluoroacetate salt

Prepared from 4-chloroaniline.

¹H NMR (d₄ MeOH): 7.97 ppm (2H, m, Ar); 7.70–7.50 (13H, m, Ar); 5.80(1H, s, CHPh); 4.21 (2H, s, CH ₂NH₂).

HPLC (Luna 2, Gradient 1): rt=3.95 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 394 (MH)⁺.

Example 20 1-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]piperidinetrifluoroacetate salt

Prepared from piperidine.

¹H NMR (d₄ MeOH): 7.97 ppm (2H, m Ar); 7.65–7.30 (7H, m, Ar); 6.10 (1H,s, CHPh); 4.21 (2H, s, CH ₂NH₂); 3.79 (1H, m, pip); 3.50 (3H, m, pip);1.70–1.21 (5H, m, pip).

HPLC (Luna 2, Gradient 1): rt=3.36 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.78 minutes, 394 (MH)⁺.

Example 211-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]-3-[(N-ethyl-N-methyl)amido]piperidinetrifluoroacetate salt

Prepared from 3-[(N-ethyl-N-methyl)amidocarbonyl]-piperidine.

¹H NMR (CD₃CN): The compound contains two chiral centres and istherefore a mixture of diastereomers, as well as exhibiting rotamers dueto the N-ethyl-N-methyl amide. 8.45–7.78 ppm (5H, m, Ar and NH);7.72–7.28 (5H, m, Ph); 6.10–5.90 (1H, m, CHPh); 4.61–4.35 (1H, m,piperidine H); 4.14 (2H, br s, CH₂NH₂); 3.97–3.66 (1H, m, piperidine H);3.50–2.35 (12H, m) 1.90–0.75 (4H, m).

HPLC (Luna 2, Gradient 1): rt=3.13 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.72 minutes, 437 (MH)⁺.

Example 22 1-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]pyrrolidinetrifluoroacetate salt

Prepared from pyrrolidine.

¹H NMR (d₄ MeOH): 7.95 ppm (2H, m, Ar); 7.72–7.34 (7H, m, Ar); 5.91 (1H,m, CHPh); 4.20 (2H, s, CH ₂NH₂); 3.80 (2H, m, pyr); 3.61 (2H, m, pyr);3.50 (2H, m, pyr); 3.19 (2H, m, pyr).

HPLC (Luna 2, Gradient 1): rt=3.06 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.57 minutes, 338 (MH)⁺.

Example 232-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]decahydroisoquinolinetrifluoroacetate salt

Prepared from decahydroisoquinoline.

¹H NMR (d₄ MeOH): 7.70 ppm (2H, br s, Ar); 7.41–7.09 (7H, m, Ar);5.95–5.78 (1H, m, CHPh); 3.95 (2H, s, CH ₂NH₂); 1.7–0.65 (16H, m,decahydroisoquinoline C(H)'s).

HPLC (Luna 2, Gradient 1): rt=4.11 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.15 minutes, 406 (MH)⁺.

Example 24 3-(Aminomethyl)benzoyl-D-phenylglycine2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared from 2,3-dihydro-6-nitroindole.

¹H NMR (d₄ MeOH): 7.91 ppm (2H, m, Ar); 7.75 (1H, s, Ar); 7.57 (4H, m,Ar); 7.34 (5H, m, Ar); 5.75 (1H, s, CHPh); 4.15 (2H, s, CH ₂NH₂); 3.75(2H, t, J=7.5 Hz, dihydroindole C(2)H₂); 3.20 (2H, t, J=7.5 Hz,dihydroindole C(3)H₂).

HPLC (Luna 2, Gradient 1): rt=2.54 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.24 minutes, 401 (MH)⁺.

Example 25 3-(Aminomethyl)benzoyl-D-phenylglycine 2,3-dihydroindolamidetrifluoroacetate salt

Prepared from 2,3-dihydroindole.

¹H NMR (d₄ MeOH): 8.92 ppm (1H, d, J=7 Hz, NH); 8.22 (1H, d, J=9.5 Hz,dihydroindole C(7)H); 7.97 (2H, m, Ar); 7.48 (3H, m, Ar); 7.19 (2H, m,Ar); 7.08 (1H, m, Ar); 6.02 (1H, m, CHPh); 4.41 (1H, m, dihydroindoleC(2)H); 4.19 (2H, s, CH ₂NH₂); 3.78 (1H, m, dihydroindole C(2)H); 3.23(1H, m, dihydroindole C(3)H); 3.07 (1H, m, dihydroindole C(3)H).

HPLC (Luna 2, Gradient 1): rt=3.79 minutes.

LC/MS (Luna 2, gradient 4): rt=2.21 minutes, 386 (MH)⁺.

Example 26 3-(Aminomethyl)benzoyl-D-phenylglycine1-methyl-2,3-dihydro-indol-6-amide bis(trifluoracetate salt)

Prepared from 6-amino-2,3-dihydro-1-methylindole.

¹H NMR (d₄ MeOH): 8.0 ppm (2H, m, Ar); 7.65 (4H, m, Ar); 7.40 (3H, m,Ar); 7.15 (2H, m, Ar); 6.95 (1H, m, Ar); 5.83 (1H, s, CHPh); 4.20 (2H,s, CH ₂NH₂); 3.42 (2H, m, dihydroindole C(2)H); 2.98 (2H, m,dihydroindole C(3)H); 2.82 (3H, s, NCH₃).

HPLC (Luna 2, Gradient 1): rt=2.80 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.88 minutes, 415 (MH)⁺.

Example 27 3-(Aminomethyl)benzoyl-D-phenylglycine3-acetylamino-4-methylphenylamide trifluoroacetate salt

Prepared from 2-methyl-5-nitroacetanilide.

¹H NMR (D₂O): 7.78–7.19 (12H, m, Ar), 5.64 (1H, s, α-CH), 4.17 (2H, s,CH ₂NH₂), 2.12 (6H, s, 2×CH ₃)

HPLC (Luna 2, Gradient 1): rt=3.10 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.56 minutes, 431 (MH⁺).

Example 28 3-(Aminomethyl)benzoyl-D-phenylglycine(R/S)-8-methyl-5,6,7,8-tetrahydronaphth-2-ylamide trifluoroacetate salt

Prepared from (R/S)-8-methyl-5,6,7,8-tetrahydronaphth-2-ylamine,synthesised as described below.

(R/S)-8-methyl-5,6,7,8-tetrahydronaphth-2-ylamine

A suspension of methyltriphenylphosphonium iodide (680 mg, 1.68 mmol) intetrahydrofuran (7 mL) was cooled to −45° C. n-Butyllithium (1.0 mL, 1.6M in hexane, 1.60 mmol) was then added dropwise, and the solution wasstirred for 1 hour. 1,2,3,4-Tetrahydro-7-nitro-1-oxonaphthalene (200 mg,1.05 mmol) in tetrahydrofuran (3 mL) was then added over 5 minutes.

The reaction mixture was allowed to warm to room temperature beforebeing quenched with water (20 mL). The solution was then extracted withdichloromethane (2×25 mL), the solvent was dried (MgSO₄) andconcentrated under reduced pressure to give a black oil. The crudeproduct was then purified by flash chromatography (ethyl acetate/hexane;1:40) to afford 5,6,7,8-tetrahydro-8-methylene-2-nitro-naphthalene as awhite solid (150 mg, 76%).

A solution of the olefin (100 mg, 0.53 mmol) in methanol (2 mL) wasstirred over 10% palladium on carbon (20 mg). The mixture was purgedwith hydrogen and stirred for 18 hrs under a balloon of hydrogen. Thereaction mixture was then filtered through celite, washing withadditional methanol, and concentrated under reduced pressure to afford(R/S)-8-methyl-5,6,7,8-tetrahydronaphth-2-ylamine as a colourless oil(75 mg, 82%).

¹H NMR (CDCl₃): 7.53 ppm (1H, d, J=8 Hz, C(4)H); 7.21 (1H, d, J=2 Hz,C(1)H); 7.18 (1H, dd, J=8, 2 Hz, C(3)H); 4.16 (2H, br s, NH₂); 3.52 (1H,sextet, J=7 Hz, CHCH₃); 3.41–3.25 (2H, m, C(5)H₂); 2.61–2.45 (2H, m,tetrahydro-naphthalene C(6)H and/or C(7)H); 2.43–2.32 (1H, m,tetrahydronaphthalene C(6) or C(7)H); 2.23–2.12 (1H, m,tetrahydronaphthalene C(6)H or C(7)H); 1.96 (3H, d, J=7 Hz, CH₃).

3-(Aminomethyl)benzoyl-D-phenylglycine(R/S)-8-methyl-5,6,7,8-tetrahydro-naphth-2-ylamide trifluoroacetate salt

¹H NMR (MeOH): 7.95 ppm (2H, br s, Ar); 7.76–7.60 (4H, m, Ar); 7.48–7.31(4H, m, Ar); 7.29–7.21 (1H, m, Ar); 6.97 (1H, d, J=8 Hz, Ar); 5.80 (1H,s, CHPh); 4.18 (2H, s, CH ₂NH₂); 2.90–2.69 (3H, m, tetrahydronaphthaleneC(5)H and C(8)H₂); 1.99–1.80 (2H, m, tetrahydronaphthalene C(6)H and/orC(7)H); 1.75–1.63 (1H, m, tetrahydronaphthalene C(6) or C(7)H);1.58–1.40 (1H, m, tetrahydro-naphthalene C(6)H or C(7)H); 1.27 (3H, d,J=7 Hz, CH₃).

HPLC (Symmetry, Gradient 2): rt=6.73 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.53 minutes, 428 (MH)⁺.

Example 29 3-(Aminomethyl)benzoyl-D-phenylglycine indan-5-ylamidetrifluoroacetate salt

Prepared from 5-aminoindane.

¹H NMR (d₄ MeOH): 8.16 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 8.15(1H, m, 3-(aminomethyl)benzoyl C(6)H); 7.96–7.54 (8H, m, Ar); 7.45 (1H,d, J=8 Hz, indane C(6)H or C(7)H); 7.33 (1H, d, J=8 Hz, indane C(6)H orC(7)H); 6.0 (1H, s, CHPh); 4.39 (2H, s, CH ₂NH₂); 3.06 (4H, q, J=7 Hz,indane C(1)H₂ and C(3)H₂); 2.26 (2H, quintet, J=7 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.02 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.42 minutes, 400 (MH)⁺.

Example 30 3-(Aminomethyl)benzoyl-D-phenylglycine 4-isopropylphenylamidetrifluoroacetate salt

Prepared from 4-isopropylaniline.

¹H NMR (d₄ MeOH): 8.17 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 8.15(1H, m, 3-(aminomethyl)benzoyl C(6)H); 7.83–7.59 (9H, m, Ar); 7.38 (2H,d, J=8.5 Hz, Ar); 6.0 (1H, s, CHPh); 4.38 (2H, s, CH ₂NH₂); 3.09 (1H,septet, J=7 Hz, CH(CH₃)₂); 1.42 (6H, d, J=7 Hz, CH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=4.21 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.48 minutes, 402 (MH)⁺.

Example 31 3-(Aminomethyl)benzoyl-D-phenylglycine (1S, 2S, 3S,5R)-isopinocamphamide trifluoroacetate salt

Prepared from (1S, 2S, 3S, 5R)-(+)-isopinocampheylamine.

¹H NMR (d₄ MeOH): 7.96 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 7.95(1H, m, 3-(aminomethyl)benzoyl C(6)H); 7.67–7.25 (7H, m, Ar); 5.70 (1H,s, CHPh); 4.28 (1H, m, isopinocampheyl C(1)H); 4.20 (2H, s, CH ₂NH₂);2.55–1.77 (5H, m, isopinocampheyl H's); 1.26 (3H, s, CH₃); 1.14 (3H, d,J=7 Hz, isopinocampheyl C(10)H₃); 1.08 (3H, s, CH₃); 1.04–0.94 (2H, m,isopinocampheyl H's).

HPLC (Luna 2, Gradient 1): rt=4.34 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.34 minutes, 420 (MH)⁺.

Example 32 3-(Aminomethyl)benzoyl-D-phenylglycine4-(1-hydroxyethyl)phenylamide trifluoroacetate salt

Prepared from 1-(4-aminophenyl)ethanol.

¹H NMR (d₄ MeOH): 7.85 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 7.84(1H, m, 3-(aminomethyl)benzoyl C(6)H); 7.56–7.05 (11H, m, Ar); 5.72 (1H,s, CHPh); 4.69 (1H, q, J=6.5 Hz, CH(OH)CH₃); 4.08 (2H, s, CH ₂NH₂); 1.31(3H, d, J=6.5 Hz, CH₃).

HPLC (Luna 2, Gradient 1): rt=3.0 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 404 (MH)⁺.

Example 33 3-(Aminomethyl)benzoyl-D-phenylglycinecis-2-aminocyclohexyl-amide bis(trifluoroacetate) salt

Prepared from cis-1,2-diaminocyclohexane.

¹H NMR (d₄ MeOH): 8.08 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 8.06(1H, m, 3-(aminomethyl)benzoyl C(6)H); 7.79–7.48 (7H, m, Ar); 5.87 (1H,s, CHPh); 4.46 (1H, m, cyclohexyl C(1)H); 4.30 (2H, s, CH ₂NH₂); 3.54(1H, m, cyclohexyl C(2)H); 2.11–1.52 (8H, m, cyclohexyl H's).

HPLC (Luna 2, Gradient 1); rt=2.40 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.08 minutes, 381 (MH)⁺.

Example 341-[3-(Aminomethyl)benzoyl-D-phenylglycinyl]4-hydroxypiperidinehydrochloride salt

Prepared from 4-hydroxypiperidine.

¹H NMR (d₄ MeOH): 7.84 ppm (1H, s, 3-(aminomethyl)benzoyl C(2)H); 7.80(1H, m, 3-(aminomethyl)benzoyl C(6)H); 7.59–7.17 (7H, m, Ar); 6.03 (1H,s, CHPh); 4.11 (2H, s, CH ₂NH₂); 3.90 (1H, m, piperidyl C(4)H); 3.62(2H, m, piperidyl C(2)H and C(6)H); 3.14–2.94 (2H, m, piperidyl C(2)Hand C(6)H); 1.93–1.16 (4H, m, piperidyl C(3)H₂ and C(5)H₂).

HPLC (Luna 2, Gradient 1): rt=2.56 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.36 minutes, 368 (MH)⁺.

Example 35 3-(Aminomethyl)benzoyl-D-phenylglycine1-acetyl-2,3-dihydro-indol-6-amide trifluoroacetate salt1-Benzyloxycarbonyl-2,3-dihydro-6-nitroindole

A solution of 6-nitroindoline (10.0 g, 0.061 mol), triethylamine (22.7mL, 0.16 mol) and dimethylaminopyridine (50 mg, cat.) in dichloromethane(130 mL) was stirred at 0° C. and benzyl chloroformate (18 mL, 0.12 mol)was added slowly. The mixture was allowed to warm to room temperatureovernight. The mixture was washed with water (50 mL), 5% aqueous HCl(100 mL), saturated aqueous NaHCO₃ (50 mL) and water (50 mL). Thedichloromethane was dried (MgSO₄) and evaporated under reduced pressureto give an orange solid. This was triturated in diethyl ether (150 ml)to give a yellow solid (12.34 g, 68%).

¹H NMR (CDCl₃): 7.80 ppm (1H, dd, J=8, 2 Hz, C(7)H); 7.35 (5H, m, Ph);7.20 (2H, m, C(4)H and C(5)H); 5.25 (2H, br s, CH ₂Ph); 4.11 (2H, t, J=8Hz, dihydroindole C(2)H₂); 3.15 (2H, t, J=8 Hz, dihydroindole C(3)H₂).

6-amino-1-benzyloxycarbonyl-2,3-dihydroindole

A mixture of 1-benzyloxycarbonyl-2,3-dihydro-6-nitroindole (1.0 g, 3.36mmol) and tin(II) chloride dihydrate (3.78 g, 16.75 mmol) in ethanol (70mL) was heated at 70° C., under an atmosphere of nitrogen, for 3 hours.The solution was cooled and the solvent evaporated under reducedpressure to give an off-white solid. The solid was partitioned betweenwater (50 mL) and ethyl actate (100 mL) and the aqueous layer basified(pH 11) with 1M sodium hydroxide solution. The mixture was filtered toremove tin salts and the ethyl acetate was separated, dried (MgSO₄) andevaporated under reduced pressure to give the amine as a yellow oil(0.89 g, 99%).

¹H NMR (CDCl₃): 7.51–7.33 ppm (6H, m, Ph+C(7)H); 6.93 (1H, d, J=8 Hz,C(4)H); 6.32 (1H, dd, J=8, 2 Hz, C(5)H); 5.28 (2H, br s, CH ₂Ph); 4.01(2H, t, J=7.5 Hz, dihydroindole C(2)H₂); 3.66 (2H, bs, NH₂); 3.05 (2H,t, J=7.5 Hz, dihydroindole C(3)H₂).

N-BOC-D-phenylglycine 1-benzyloxycarbonyl-2,3-dihydroindol-6-amide

A solution of N-BOC-D-phenylglycine (0.83 g, 3.28 mmol),1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (0.75 g,3.9 mmol), 1-hydroxy-7-azabenzotriazole (0.54 g, 3.9 mmol) and4-(N,N-dimethylamino)pyridine (10 mg, cat.) in dimethylformamide (20 mL)was stirred at room temperature and a solution of the above amine (0.88g, 3.28 mmol) in dimethylformamide (20 mL) was added and the mixtureallowed to stir overnight. The dimethylformamide was evaporated underreduced pressure and the resulting oil partitioned between water (50 mL)and ethyl acetate (50 mL). The ethyl acetate was washed with 5% aqueousHCl (10 mL) and saturated aqueous NaHCO₃ (10 mL), dried (MgSO₄) andevaporated under reduced pressure to give the amide as a golden foam(1.6 g, 97%).

¹H NMR (CDCl₃): 7.43–7.10 ppm (13H, m, Ar): 6.85 (1H, d, J=6 Hz, NH);5.61 (1H, br s, NH); 5.03 (2H, br s, CH ₂Ph); 3.85 (2H, t, J=7 Hz,dihydroindole C(2)H₂); 2.85 (2H, t, J=8 Hz, dihydroindole C(3)H₂); 1.19(9H, s, ^(t)Bu).

D-phenylglycine 1-benzyloxycarbonyl-2,3-dihydroindol-6-amidetrifluoroacetate salt

Trifluoroacetic acid (5 mL) was added to a solution of the above foam indichloromethane (20 mL) and the solution was allowed to stir for 2 hoursat room temperature. The solvent was evaporated under reduced pressureto give the amine trifluoracetate salt as a red foam (1.5 g, 91%) whichwas used without further purification.

3-(N-BOC-Aminomethyl)benzoyl-D-phenylglycine(1-benzyloxycarbonyl-2,3-dihydro)-indol-6-amide

A solution of 3-(N-BOC-aminomethyl)benzoic acid (0.798 g, 3.2 mmol),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.73 g,3.8 mmol), 1-hydroxy-7-azabenzotriazole (0.52 g, 3.8 mmol) andtriethylamine (1.0 mL, 7.2 mmol) in dimethylformamide (10 mL) wasstirred at room temperature and a solution of the above amine (1.5 g,3.0 mmol) in dimethylformamide (5 mL) was added. The mixture was stirredovernight before the dimethylformamide was evaporated under reducedpressure, and the resulting oil partitioned between water (50 mL) andethyl acetate (50 mL). The ethyl acetate layer was washed with 5%aqueous HCl (10 mL) and saturated aqueous NaHCO₃ (10 mL), dried (MgSO₄)and evaporated under reduced pressure to give a yellow solid.

¹H NMR (CDCl₃): 7.75–7.22 ppm (17H, m, Ar): 7.05 (1H, d, J=5.5 Hz, NH);5.74 (1H, d, J=6 Hz, CHPh); 5.21 (2H, s, OCH ₂Ph); 4.89 (1H, br s, NH);4.32 (2H, d, J=6 Hz, CH₂NHBOC); 4.02 (2H, t, J=8 Hz, dihydroindoleC(2)H₂); 3.05 (2H, t, J=8 Hz, dihydroindole C(3)H₂); 1.4 (9H, s,^(t)Bu).

3-(N-BOC-Aminomethyl)benzoyl-D-phenylglycine 2,3-dihydroindol-6-amide

A solution of the above solid in methanol (50 mL) was stirred over 10%Pd/C (500 mg) under an atmosphere of H₂ and heated under reflux for 2hours. The mixture was cooled, filtered and the solvent evaporated underreduced pressure to provide the unprotected dihydroindole as a yellowfoam (1.4 g, 88%) which was used without further purification.

3-(Aminomethyl)benzoyl-D-phenylglycine 1-acetyl-2,3-dihydroindol-6-amidetrifluoroacetate salt

A solution of the dihydroindole (500 mg, 1.0 mmol) and triethylamine(0.28 mL, 2 mmol) in dichloromethane (20 mL) was stirred at 0° C. andacetyl chloride (86 mg, 1.1 mmol) was added dropwise, then left to stirovernight. The mixture was washed with 5% aqueous HCl (10 mL) and theorganic phase was dried (MgSO₄) and evaporated. The residue was purifiedby flash column chromatography (ethyl acetate/hexane, 1:1) to give ayellow oil. The oil was dissolved in dichloromethane (20 mL) and treatedwith trifluoroacetic aid (5 mL). After stirring for 2 hours the solventwas evaporated under redued pressure to an oil, which after trituratingwith diethyl ether gave the amine as its trifluoroacetate salt as awhite solid (337 mg, 61%).

¹H NMR (d₄ MeOH): 8.30 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.60 (4H, m,Ar); 7.39 (4H, 3, m, Ar); 7.22 (1H, d, J=10 Hz, Ar); 5.82 (1H, s, CHPh);4.2 (2H, s, CH ₂NH₂); 4.15 (2H, t, J=7 Hz, dihydroindole C(2)H₂); 3.17(2H, t, J=7 Hz, dihydroindole C(3)H₂); 2.25 (3H, s, CH₃).

HPLC (Luna 2, Gradient 1): rt=3.39 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.72 minutes, 443 (MH)⁺.

Examples 36–60 were prepared from the intermediate3-(N-BOC-aminomethyl)-benzoyl-D-phenylglycine 2,3-dihydroindol-5-amide,described for Example 29, and the appropriate carboxylic acid orderivative, using standard chemical methods and protecting otherfunctionality where required.

Example 36 3-(Aminomethyl)benzoyl-D-phenylglycine1-propanoyl-2,3-dihydro-indol-6-amide trifluoroacetate salt

Prepared using propanoyl chloride.

¹H NMR (d₄ MeOH): 8.58 ppm (1H, d, J=1.2 Hz, dihydroindole C(7)H); 8.18(2H, m, Ar); 7.82 (4H, m, Ar); 7.59 (4H, m, Ar); 7.37 (1H, m, Ar); 6.03(1H, s, CHPh); 4.39 (2H, s, CH ₂NH₂); 4.31 (2H, t, J=9 Hz, dihydroindoleC(2)H); 3.37 (2H, t, J=9 Hz, dihydroindole C(3)H); 2.73 (2H, q, J=7.5Hz, CH ₂CH₃); 1.47 (3H, t, J=7.5 Hz, CH₂CH ₃).

HPLC (Luna 2, Gradient 1): rt=3.55 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.94 minutes, 457 (MH)⁺.

Example 37 3-(Aminomethyl)benzoyl-D-phenylglycine1-(2-methyl-propanoyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using 2-methylpropanoyl chloride.

¹H NMR (d₄ MeOH): 8.32 ppm (1H, s, dihydroindole C(7)H); 7.98 (2H, m,Ar); 7.60 (4H, m, Ar); 7.43 (4H, m, Ar); 7.18 (1H, m, Ar); 5.83 (1H, s,CHPh); 4.21 (4H, m, CH ₂NH₂ and dihydroindole C(2)H); 3.18 (2H, t, J=9Hz, dihydroindole C(3)H), 2.95 (1H, m, CH(CH₃)₂); 1.22 (6H, d, J=8 Hz,CH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=3.74 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 471 (MH)⁺.

Example 38 3-(Aminomethyl)benzoyl-D-phenylglycine1-D-alaninoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using D-alanine.

¹H NMR (d₄ MeOH): 8.40 ppm (1H, s, Ar); 8.01 (2H, m, Ar); 7.65 (4H, m,Ar); 7.45 (4H, m, Ar); 7.25 (1H, d, J=10 Hz, Ar); 5.85 (1H, s, CHPh);4.4 (1H, q, J=0.7 Hz, alaninyl CHNH₂); 4.25 (2H, s, ArCH ₂NH₂); 4.25(2H, t, J=8 Hz, dihydroindole C(2)H₂); 3.28 (2H, t, J=8 Hz,dihydroindole C(3)H₂); 1.65 (3H, d, J=7 Hz, CH₃).

HPLC (Luna 2, Gradient 1): rt=2.85 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.35 minutes, 472 (MH)⁺.

Example 39 3-(Aminomethyl)benzoyl-D-phenylglycine1-L-alaninoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using L-alanine.

¹H NMR (d₄ MeOH): 8.43 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.63 (4H, m,Ar); 7.45 (4H, m, Ar); 7.25 (1H, d, J=10 Hz, Ar); 5.85 (1H, s, CHPh);4.35 (1H, q, J=7 Hz, alaninyl CHNH₂); 4.25 (2H, t, J=7.5 Hz, indolineC(2)H₂); 4.2 (2H, s, CH ₂NH₂); 3.25 (2H, t, J=8 Hz, indoline C(3)H₂);1.6 (3H, d, J=7 Hz, CH ₃).

HPLC (Luna 2, Gradient 1): rt=2.84 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 472 (MH)⁺.

Example 40 3-(Aminomethyl)benzoyl-D-phenylglycine1-(N-acetyl-D-alaninoyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using N-acetyl-D-alanine.

¹H NMR (d₄ MeOH): 8.33 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.61 (4H, m,Ar); 7.40 (4H, m, Ar); 7.18 (1H, d, J=9 Hz, Ar); 5.83 (1H, s, CHPh);4.70 (1H, br m, CHNHAc); 4.38 (1H, m, indoline C(2)H); 4.21 (2H, s, CH₂NH₂); 4.20 (1H, t, J=8 Hz indoline C(2)H); 3.2 (2H, t, J=8 Hz, indolineC(3)H₂); 2.01 (3H, s, COCH ₃); 1.4 (3H, d, J=7 Hz, CH₃).

HPLC (Luna 2, Gradient 1): rt=3.24 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 514 (MH)⁺.

Example 41 3-(Aminomethyl)benzoyl-D-phenylglycine1-(N-acetyl-L-alaninoyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using N-acetyl-L-alanine.

¹H NMR (d₄ MeOH): 8.33 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.62 (4H, m,Ar); 7.38 (4H, m, Ar); 7.18 (1H, d, Ar); 5.83 (1H, s, CHPh); 4.70 (1H,m, CHNHAc); 4.35 (1H, m, dihydroindole C(2)H); 4.2 (2H, s, CH ₂NH₂); 4.2(1H, m, dihydroindole C(2)H); 3.2 (2H, t, J=8 Hz, dihydroindole C(3)H₂);2.0 (3H, s, COCH₃); 1.4 (3H, d, J=7 Hz, CH₃).

HPLC (Luna 2, Gradient 1): rt=3.19 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.67 minutes, 514 (MH)⁺.

Example 42 3-(Aminomethyl)benzoyl-D-phenylglycine1-aminoacetyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using glycine.

¹H NMR (d₄ MeOH): 8.41 (1H, s, dihydroindole C(7)H); 7.97 (2H, br s,Ar); 7.58 (4H, m, Ar); 7.22 (1H, d, J=8 Hz, Ar); 5.84 (1H, s, CHPh);4.20 (2H, s, CH ₂NH₂); 4.15 (2H, t, J=9 Hz, dihydroindole C(2)H); 4.04(2H, s, COCH ₂NH₂); 3.23 (2H, t, J=9 Hz, dihydroindole C(3)H).

HPLC (Luna 2, Gradient 1): rt=2.77 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.24 minutes, 458 (MH)⁺.

Example 43 3-(Aminomethyl)benzoyl-D-phenylglycine1-(3-methylbutanoyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using 3-methylbutanoyl chloride.

¹H NMR (d₄ MeOH): 8.40 ppm (1H, s, Ar); 8.02 (2H, m, Ar); 7.67 (4H, m,Ar); 7.22 (1H, d, J=11 Hz, Ar); 5.90 (1H, s, CHPh); 4.27 (2H, s, CH₂NH₂); 4.22 (2H, t, J=8 Hz, indoline C(2)H₂); 3.22 (2H, t, J=8 Hz,indoline C(3)H₂); 2.45 (2H, d, J=7 Hz, COCH₂); 2.28 (1H, septet, J=7 Hz,CHMe₂); 1.1 (6H, d, J=7 Hz, CH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=4.18 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.15 minutes, 485 (MH)⁺.

Example 44 3-(Aminomethyl)benzoyl-D-phenylglycine1-(benzyloxy)-acetyl-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using 2-benzyloxyacetyl chloride.

¹H NMR (d₄ MeOH): 8.40 ppm (1H, s, Ar); 8.02 (2H, m, Ar); 7.65 (5H, m,Ar); 7.45 (10H, m, Ar); 7.22 (1H, d, J=10 Hz, Ar); 5.91 (1H, s, CHPh);4.73 (2H, s, COCH); 4.35 (1H, q, CHNH₂); 4.37 (2H, s, CH ₂Ph); 4.25 (2H,s, CH ₂NH₂); 4.12 (2H, t, J=7.5 Hz, indoline C(2)H₂); 3.2 (2H, t, J=7.5Hz, indoline C(3)H₂).

HPLC (Luna 2, Gradient 1): rt=4.25 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.15 minutes, 549 (MH)⁺.

Example 45 3-(Aminomethyl)benzoyl-D-phenylglycine1-L-threoninoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using L-threonine.

¹H NMR (d₄ MeOH): 8.31 ppm (1H, s, Ar); 7.80 (2H, m, Ar); 7.45 (4H, m,Ar); 7.25 (4H, m, Ar); 7.05 (1H, d, Ar); 5.65 (1H, s, CHPh); 4.10 (2H,t, J=8 Hz, indoline C(2)H₂); 4.02 (2H, s, CH ₂NH₂); 3.11 (2H, t, J=8 Hz,indoline C(3)H₂); 1.21 (3H, d, CH₃); other signals obscured by solvent.

HPLC (Luna 2, Gradient 1): rt=2.84 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.65 minutes, 502 (MH)⁺.

Example 46 3-(Aminomethyl)benzoyl-D-phenylglycine1-L-prolinoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using L-proline.

¹H NMR (d₄ MeOH): 8.47 ppm (1H, s, Ar); 8.05 (2H, m, Ar); 7.75–7.65 (4H,m, Ar); 7.56–7.47 (4H, m, Ar); 7.30 (1H, d, J=9 Hz, Ar); 5.91 (1H, s,CHPh); 4.73 (1H, t, J=6.5 Hz, proline C(2)H); 4.25 (4H, m, CH₂NH₂ andindoline C(2)H₂); 3.65–3.32 (3H, m, indoline C(3)H₂ and proline C(5)H);2.70 (1H, m, proline C(5)H); 2.33–2.15 (4H, m, proline C(3)H₂ andC(4)H₂).

HPLC (Luna 2, Gradient 1): rt=2.98 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 498 (MH)⁺.

Example 47 3-(Aminomethyl)benzoyl-D-phenylglycine1-((S)-2-hydroxy-propanoyl)-2,3-dihydroindol-6-amide trifluoroacetatesalt

Prepared using (S)-2-hydroxypropanoic acid.

¹H NMR (d₄ MeOH): 8.33 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.66–7.56 (4H,m, Ar); 7.45–7.37 (4H, m, Ar); 7.18 (1H, d, J=9 Hz, Ar); 5.83 (1H, s,CHPh); 4.58 (1H, m, CHOH); 4.31 (1H, m, indoline C(2)H); 4.21 (2H, s, CH₂NH₂); 4.15 (1H; m, indoline C(2)H); 3.18 (2H, t, J=8 Hz, indolineC(3)H₂); 1.4 (3H, d, J=7 Hz, CH₃).

HPLC (Luna 2, Gradient 1): rt=3.31 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.72 minutes, 473 (MH)⁺.

Example 48 3-(Aminomethyl)benzoyl-D-phenylglycine1-D-prolinoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using D-proline.

¹H NMR (d₄ MeOH): 8.41 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.64–7.57 (4H,m, Ar); 7.48–7.39 (4H, m, Ar); 7.23 (1H, d, J=11 Hz, Ar); 5.82 (1H, s,CHPh); 4.63 (1H, m, proline C(2)H); 4.24 (4H, m, CH₂NH₂ and indolineC(2)H₂); 3.52–3.24 (3H, m, indoline C(3)H₂ and proline C(5)H); 2.63 (1H,m, proline C(5)H); 2.23–2.08 (4H, m, proline C(3)H₂ and C(4)H₂).

HPLC (Luna 2, Gradient 1): rt=2.98 minutes.

HPLC (Symmetry, Gradient 2): rt=4.87 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 498 (MH)⁺.

Example 49 3-(Aminomethyl)benzoyl-D-phenylglycine1-L-serinoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using L-serine.

¹H NMR (d₄ MeOH): 8.40 ppm (1H, s, Ar); 7.95 (2H, m, Ar); 7.64–7.57 (4H,m, Ar); 7.47–7.39 (4H, m, Ar); 7.23 (1H, d, J=10 Hz, Ar); 5.81 (1H, s,CHPh); 4.4 (1H, dd, J=12 Hz, 4 Hz, serine CH _(a)H_(b)OH); 4.25 (2H, t,J=7 Hz, indoline C(2)H₂); 4.20 (2H, s, CH ₂NH₂); 4.05 (1H, dd, J=12, 6Hz, serine CH_(a) H _(b)OH); 3.91 (1H, m, serine CHNH₂); 3.25 (2H, t,J=7 Hz, indoline C(3)H₂).

HPLC (Luna 2, Gradient 1): rt=2.84 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.35 minutes, 488 (MH)⁺.

Example 50 3-(Aminomethyl)benzoyl-D-phenylglycine1-D-serinoyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using D-serine.

¹H NMR (d₄ MeOH): 8.42 ppm (1H, s, Ar); 7.97 (2H, m, Ar); 7.64–7.57 (4H,m, Ar); 7.47–7.39 (4H, m, Ar); 7.23 (1H, d, J=9 Hz, Ar); 5.82 (1H, s,CHPh); 4.41 (1H, dd, J=12, 4 Hz, serine CH _(a)H_(b)OH); 4.25 (2H, t,J=7.5 Hz, indoline C(2)H₂); 4.2 (2H, s, CH ₂NH₂); 4.05 (1H, dd, J=12, 6Hz, serine CH_(a) H _(b)OH); 3.9 (1H, mserine CHNH₂); 3.25 (2H, t, J=7.5Hz, indoline C(3)H₂).

HPLC (Luna 2, Gradient 1): rt=2.78 minutes.

HPLC (Symmetry, Gradient 2): rt=4.61 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.65 minutes, 488 (MH)⁺.

Example 51 3-(Aminomethyl)benzoyl-D-phenylglycine1-(3-pyridyl-acetyl)-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared using 3-pyridylacetic acid.

¹H NMR (d₃ acetonitrile): 8.91 ppm (1H, br s, Ar), 8.73–8.55 (2H, m,Ar), 8.35 (1H, br s, Ar), 8.15 (1H, d, J=10 Hz, Ar), 8.05–7.95 (2H, m,Ar), 7.80 (1H, d, J=10 Hz, Ar), 7.74–7.15 (10H, m, Ar & 2× amide NH),5.69 (1H, d, J=7 Hz, CHPh), 4.25–4.12 (4H, m, ArCH ₂N & dihydroindoleC(2)H₂), 3.98 (2H, s, C(O)CH ₂Py), 3.17 (2H, t, J=8 Hz, dihydroindoleC(3)H₂).

HPLC (Luna 2, Gradient 1): rt=2.96 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.35 minutes, 520 (MH⁺).

Example 52 3-(Aminomethyl)benzoyl-D-phenylglycine1-(N-acetyl)-aminoacetyl-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using N-acetylglycine.

¹H NMR (d₄ MeOH): 8.31 ppm (1H, s, Ar); 7.95 (2H, m, Ar); 7.64–7.57 (4H,m, Ar); 7.43–7.38 (4H, m, Ar); 7.18 (1H, d, J=10 Hz, Ar); 5.81 (1H, s,CHPh); 4.23–4.11 (6H, m, ArCH₂NH₂, aminoacetyl CH₂ and dihydroindoleC(2)H₂); 3.21 (2H, t, J=7 Hz, dihydroindole C(3)H₂); 2.07 (3H, s,COCH₃).

HPLC (Luna 2, Gradient 1): rt=3.33 minutes.

HPLC (Symmetry, Gradient 2): rt=5.20 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.59 minutes, 500 (MH)⁺.

Example 53 3-(Aminomethyl)benzoyl-D-phenylglycine1-(hydroxyacetyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using 2-benzyloxyacetic acid.

¹H NMR (d₄ MeOH): 8.25 ppm (1H, s, Ar); 7.85 (2H, m, Ar); 7.54–7.47 (4H,m, Ar); 7.35–7.26 (4H, m, Ar); 7.10 (1H, d, J=11 Hz, Ar); 4.21 (2H, s,CH ₂OH); 4.10 (2H, s, CH ₂NH₂); 3.95 (2H, t, J=7.5 Hz, dihydroindoleC(2)H₂); 3.21 (2H, t, J=7.5 Hz, dihydroindole C(3)H₂).

HPLC (Luna 2, Gradient 1): rt=3.23 minutes.

HPLC (Symmetry, Gradient 2): rt=5.26 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.67 minutes, 500 (MH)⁺.

Example 54 3-(Aminomethyl)benzoyl-D-phenylglycine1-phenylacetyl-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared using phenylacetic acid.

¹H NMR (d₃ acetonitrile): 8.78 (1H, br s, Ar), 8.23 (1H, br s, Ar), 7.90(2H, s, Ar), 7.73 (1H, d, J=10 Hz, Ar), 7.60–7.01 (14H, m, Ar & 2× amideNH), 5.60 (1H, d, J=7 Hz, CHPh), 4.10–3.97 (4H, m, ArCH ₂N &dihydroindole C(2)H₂), 3.71 (2H, s, PhCH ₂), 2.99 (2H, t, J=8 Hz,dihydroindole C(3)H₂).

HPLC (Luna 2, Gradient 1): rt=4.17 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.26 minutes, 519 (MH⁺).

Example 55 3-(Aminomethyl)benzoyl-D-phenylglycine1-(methylamino)-acetyl-2,3-dihydroindol-6-amide bis(trifluoroacetate)salt

Prepared using sarcosine.

¹H NMR (d₄ MeOH): 8.39 ppm (1H, s, indoline C(7)H); 7.95 (2H, br s,3-(aminomethyl)phenyl C(2)H and C(6)H); 7.72–7.53 (4H, m, Ar); 7.47–7.31(4H, m, Ar); 7.24 (1H, d, J=10 Hz, indoline C(4)H or C(5)H); 5.82 (1H,br s, CHPh); 4.20 (2H, s, CH ₂NH₂ or C(O)CH ₂NHMe); 4.15 (2H, s, CH ₂NH₂or C(O)CH ₂NHMe); 4.10 (2H, t, J=9 Hz, indoline C(2)H₂); 3.25 (2H, t,J=9 Hz, indoline C(3)H₂); 2.81 (3H, s, CH₃).

HPLC (Symmetry C8, Gradient 2): rt=4.75 min.

LCMS (Luna 2, Gradient 4): rt=1.45 min, 472 (MH)⁺.

Example 56 3-(Aminomethyl)benzoyl-D-phenylglycine3-aminopropionyl-2,3-dihydroindol-6-amide bis(trifluoracetate) salt

Prepared using β-alanine.

¹H NMR (D₂O): 7.98 ppm (1H, s, indoline C(7)H); 7.72 (2H, br s,3-(aminomethyl)phenyl C(2)H and C(6)H); 7.60–7.30 (7H, m, Ar); 7.08 (1H,d, J=10 Hz, indoline C(4)H or C(5)H); 6.95 (1H, d, J=10 Hz, indolineC(4)H or C(5)H); 5.57 (1H, s, CHPh); 4.09 (2H, s, ArCH ₂NH₂); 3.82 (2H,t, J=7 Hz, indoline C(3)H₂); 3.20 (2H, t, J=4.5 Hz, C(O)CH ₂CH₂NH₂);2.95 (2H, t, J=7 Hz, indoline C(3)H₂); 2.71 (2H, t, J=4.5 Hz, C(O)CH₂CH₂NH₂).

HPLC (Symmetry C8, Gradient 2): rt=4.80 minutes.

LCMS (Luna 2, Gradient 4): rt=1.53 minutes, 472 (MH)⁺.

Example 57 3-(Aminomethyl)benzoyl-D-phenylglycine1-(4-pyridyl-acetyl)-2,3-dihydroindol-6-amide bis-trifluoroacetate salt

Prepared using 4-pyridylacetic acid.

¹H NMR (CD₃CN): 8.91 (1H, br s, Ar), 8.73–8.55 (2H, m, Ar), 8.35 (1H, brs, Ar), 8.15 (1H, d, J=10 Hz, Ar), 8.05–7.95 (2H, m, Ar), 7.80 (1H, d,J=10 Hz, Ar), 7.74–7.15 (10H, m, Ar & 2× amide NH), 5.69 (1H, d, J=7 Hz,CHPh), 4.25–4.12 (4H, m, PhCH ₂N & dihydroindole C(2)H₂), 3.98 (2H, s,C(O)CH ₂Py), 3.17 (2H, t, J=8 Hz, dihydroindole C(3)H₂).

HPLC (Symmetry, Gradient 2): rt=5.43 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.56 minutes, 520 (MH)⁺.

Example 58 3-(Aminomethyl)benzoyl-D-phenylglycine1-(imidazol-4-ylacetyl)-2,3-dihydroindol-6-amide bis(trifluoroacetate)salt

Prepared using imidazol-4-ylacetic acid.

¹H NMR (D₂O): 7.75 ppm (1H, br s, NH); 7.49 (2H, br s, Ar); 7.28 (1H, d,J=8 Hz, Ar); 7.24–7.12 (9H, m, Ar); 6.92 (1H, d, J=8 Hz, Ar); 6.74 (1H,d, J=8 Hz, Ar); 6.28 (1H, s, NH); 5.38 (1H, s, CHPh); 3.87 (2H, s,ArCH₂NH₂); 3.72 (2H, d, J 8=Hz, dihydroindole C(2)H₂); 3.52 (2H, br s,CH₂Im); 2.70 (2H, t, J=8 Hz, dihydroindole C(3)H₂).

HPLC (Symmetry, Gradient 2): rt=4.89 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.45 minutes, 509 (MH)⁺.

Example 59 3-(Aminomethyl)benzoyl-D-phenylglycine1-(2-aminothiazol-4-yl)-acetyl-2,3-dihydroindol-6-amide dihydrochloride

Prepared using (2-formamidothiazol-4-yl)acetic acid.

¹H NMR (D₂O): 7.77 ppm (1H, br s, NH); 7.51 (2H, br s, Ar); 7.29 (1H, d,J=8 Hz, Ar); 7.24–7.03 (9H, m, Ar); 6.91 (1H, d, J=8 Hz, Ar); 6.72 (1H,d, J=8 Hz, Ar); 6.22 (1H, s, NH); 5.32 (1H, s, CHPh); 3.85 (2H, s, ArCH₂NH₂); 3.73 (2H, d, J=8 Hz, dihydroindole C(2)H₂); 3.56 (2H, br s,CH₂Thz); 2.76 (2H, t, J=8 Hz, dihydroindole C(3)H₂).

HPLC (Symmetry, Gradient 2): rt=5.03 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.51 minutes, 541 (MH)⁺.

Example 60 3-(Aminomethyl)benzoyl-D-phenylglycine1-(2-formylaminothiazol-4-yl)acetyl-2,3-dihydroindol-6-amidetrifluoroacetate salt

Prepared using (2-formylaminothiazol-4-yl)acetic acid.

¹H NMR (D₂O): 8.30 ppm (1H, s, NCHO); 7.90 (1H, br s, ArNH); 7.64 (2H,br s, Ar); 7.42 (1H, d, J=8 Hz, Ar); 7.38–7.26 (9H, m, Ar & NH); 7.01(1H, d, J=8 Hz, Ar); 6.96 (1H, d, J=8 Hz, Ar); 6.82 (1H, s, NH); 5.50(1H, s, CHPh); 4.06 (2H, s, ArCH ₂NH₂); 3.90 (2H, d, J=8 Hz,dihydroindole C(2)H₂); 3.64 (2H, br s, CH ₂Thz); 2.90 (2H, t, J=8 Hz,dihydroindole C(3)H₂).

HPLC (Symmetry, Gradient 2): rt=5.75 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.10 minutes, 569 (MH)⁺.

Example 61 3-(Aminomethyl)benzoyl-D/L-(4-aminomethyl)phenylglycineindan-5-amide bis(trifluoroacetate) salt Methyl 4-bromophenylacetate

Thionyl chloride (18 mL, 0.25 mol) was added dropwise to a solution of4-bromo-phenylacetic acid (50 g; 0.23 mol) in methanol (250 mL). Theresulting mixture was stirred at room temperature for 1 hour before themethanol was removed in vacuo. Ethyl acetate (300 mL) was added and theresulting solution was washed with water (3×150 mL) and 1M aqueousNaHCO₃ (1×150 mL), dried (MgSO₄) and evaporated to give the ester (52.8g; 100%) as an orange oil which was used without further purification.

¹H NMR (CDCl₃): 7.38 ppm (2H, d, J=8.4 Hz, C(2)H and C(6)H); 7.09 (2H,d, J=8.4 Hz, C(3)H and C(5)H); 3.63 (3H, s, OMe); 3.51 (2H, s, CH₂).

Methyl 4-cyanophenylacetate

Zinc cyanide (10.4 g, 0.088 mol) andtetrakis-(triphenylphosphine)palladium(0) (5 g, 4.4 mmol) were added toa solution of methyl 4-bromophenylacetate (20 g, 0.088 mol) indimethylformamide (150 mL). The resulting mixture was stirred at 80° C.for 5 hours, then allowed to cool to room temperature. Toluene (500 mL)and 1M aqueous ammonia (500 mL) were added, the layers were separatedand the organic layer washed with brine (100 mL) and dried (MgSO₄).Evaporation of the solvents afforded an off-white solid, which waspurified by silica gel chromatorgraphy to afford the cyano-compound as awhite solid (11.3 g; 73%).

¹H NMR (CDCl₃): 7.65 ppm (2H, d, J=8.4 Hz, C(3)H and C(5)H); 7.42 (2H,d, J=8.1 Hz, C(2)H and C(6)H); 3.74 (3H, s, OMe); 3.72 (2H, s, CH₂).

4-Cyanophenylacetic acid

A solution of methyl 4-cyanophenylacetate (23.9 g; 0.136 mol) in ethanol(250 mL) was stirred at room temperature and a solution of sodiumhydroxide (6.0 g; 0.15 mol) in water (25 mL) was added. After 2 hoursthe ethanol was removed in vacuo. Ethyl acetate (300 mL) and 5% aqueousHCl (300 mL) were added and the layers were separated. The aqueous layerwas extracted with ethyl acetate (300 mL) and the combined organiclayers were dried (MgSO₄) and evaporated in vacuo to give the acid (21.6g; 99%) which was used without further purification.

¹H NMR (CDCl₃): 7.57 ppm (2H, d, J=8.3 Hz, C(3)H and C(5)H); 7.34 (2H,d, J=8.2 Hz, C(2)H and C(6)H); 3.64 (2H, s, CH₂).

4-(N-BOC-aminomethyl)phenylacetic acid

A solution of 4-cyanophenylacetic acid (12.11 g, 0.075 mol) in water(163 mL) and concentrated aqueous ammonia (40 mL) was stirred at roomtemperature and Raney nickel (6.3 g) was added. The resulting suspensionwas stuirred under a hydrogen atmosphere for 24 hours before thereaction mixture was filtered through celite and evaporated in vacuo togive crude 4-(aminomethyl)-phenylacetic acid (12.57 g; 100%) as a paleblue solid.

A solution of the crude amino acid (12.57 g, 0.075 mol) in water (50 mL)and 1,4-dioxane (50 mL) was stirred at room temperature and sodiumhydroxide (3 g, 0.075 mol) and di-^(t)butyl dicarbonate (16.4 g, 0.075mol) were added simultaneously. After 24 hours the 1,4-dioxane wasremoved in vacuo and the aqueous layer was acidified with saturatedaqueous citric acid (200 mL). The solution was extracted with ethylacetate (3×150 mL) and the combined organic layers were dried (MgSO₄)and evaporated in vacuo to give the N-BOC-amine (17.6 g, 88%) as a whitesolid which was used without further purification.

¹H NMR (CDCl₃): 7.00 ppm (4H, m, Ar); 4.65 (1H, br s, N—H); 4.09 (2H, d,J=6 Hz, CH ₂NH); 3.43 (2H, s, CH₂); 1.25 (9H, s, ^(t)Bu).

Methyl 4-(N-BOC-aminomethyl)phenylacetate

1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (34.8 g,0.18 mol) and 4-(N,N-dimethylamino)pyridine (220 mg, 1.8 mmol) wereadded to a solution of 4-(N-BOC-aminomethyl)phenylacetic acid (47.8 g,0.18 mol) in methanol (200 ml). After stirring for 18 hours the methanolwas removed in vacuo and the reaction mixture partitioned between ethylacetate (200 mL) and saturated aqueous citric acid (200 mL). The organicphase was separated and washed with saturated aqueous NaHCO₃ (200 mL)and brine (200 mL), dried (MgSO₄) and evaporated to give the methylester (49.8 g; 99%).

¹H NMR (CDCl₃): 7.42 ppm (4H, s, Ar); 5.02 (1H, br s, N—H); 4.48 (2H, d,J=5.7 Hz, CH ₂NH); 3.87 (3H, s, OMe); 3.79 (2H, s, CH₂); 1.64 (9H, s,^(t)Bu).

Methyl[4-(N-BOC-aminomethyl)phenyl]-α-azidoacetate

A solution of methyl 4-(N-BOC-aminomethyl)phenylacetate (9.34 g; 0.033mol) in THF (100 mL) was stirred under argon at −78° C. and potassiumbis(trimethylsilyl)amide (16.7 g, 0.084 mol) in THF (50 mL) was added.After stirring for 30 minutes, 2,4,6-triisopropylbenzene-sulfonyl azide(31.1 g, 0.101 mol) was added as a solid. After 5 minutes, acetic acid(10 mL, 0.175 mol) was added and the reaction warmed to roomtemperature. The reaction mixture was then partitioned between ethylacetate (500 mL) and water (500 mL), separated and the organic layerdried (MgSO₄). Evaporation of the solvent and purification of theresidue by silica gel chromatography afforded the azide (7.1 g, 67%).

¹H NMR (CDCl₃): 7.28 ppm (4H, s, Ar); 4.92 (1H, s, CHN₃); 4.25 (2H, s,CH ₂NH); 3.69 (3H, s, OMe); 1.38 (9H, s, ^(t)Bu).

Methyl α-amino-[4-(N-BOC-aminomethyl)phenylacetate

A solution of methyl(4-(N-BOC-aminomethyl)phenyl]-α-azidoacetate (7.1 g,0.022 mol) in ethyl acetate (50 mL) was stirred over palladium on carbon(5%). The reaction vessel was taken up to 250 psi with hydrogen for 17hours. The reaction mixture was filtered through celite and evaporatedin vacuo to give the amine (6.47 g, 100%) as a pale solid.

¹H NMR (CDCl₃): 7.20 ppm (2H, m, Ar); 7.12 (2H, m, Ar); 4.81 (1H, br s,NH); 4.45 (1H, s, CH); 4.18 (2H, d, J=6 Hz, CH ₂NH); 3.54 (3H, s, OMe);2.09 (2H, br s, NH₂); 1.30 (9H, s, ^(t)Bu).

Methylα-(N-benzyloxycarbonyl-amino)-[4-(N-BOC-aminomethyl)phenyl]acetate

A solution of the amine (530 mg, 1.8 mmol) in tetrahydrofuran (15 mL)was treated with triethylamine (0.25 mL, 1.8 mmol) and benzylchloroformate (0.26 mL, 1.8 mmol) and allowed to stir at roomtemperature for 1 hour. The reaction was diluted with ethyl acetate (40mL), washed with brine (2×25 mL), dried (MgSO₄) and concentrated underreduced pressure to afford a yellow oil. The benzyloxycarbonyl ester waspurified by flash chromatography on silica gel (ethyl acetate/hexane1:1) to give a yellow solid (312 mg, 66%).

¹H NMR (CDCl₃): 7.32–7.15 ppm (9H, m, 9 Ar); 5.80 (1H, br s, NH); 5.30(1H, d, J=9.6 Hz, CH); 5.01 (2H, s, CH₂Ph); 4.22 (2H, d, J=7.2 Hz, CH₂NHBoc); 3.63 (3H, s, OCH3); 1.39 (9H, s, ^(t)Bu).

D/L-α-(N-benzyloxycarbonyl)-[4-(N-BOC-aminomethyl) phenyl]glycine

A solution of the ester (356 mg, 0.83 mmol) in tetrahydrofuran (15 mL)was treated with 1 M LiOH (1.7 mL, 1.7 mmol) and heated at reflux for 3hours. The solvent was removed under reduced pressure and the residuediluted with water (20 mL). The pH was reduced to 4 using 5% aqueous HCland the aqueous phase was extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure to afford the acid as a yellow solid (273 mg, 79%)which was carried forward without further purification.

D/L-α-(N-benzyloxycarbonyl)-[4-(N-BOC-aminomethyl)phenyl]glycineindan-5-amide

A solution of the acid (173 mg, 0.42 mmol) in dimethylformamide (15 ml)was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (80 mg, 0.42 mmol), 1-hydroxy-7-azabenzotriazole (57 mg,0.42 mmol), 5-aminoindane (56 mg, 0.42 mmol) and4-(N,N-dimethylamino)pyridine (5 mg) and stirred overnight at roomtemperature before being partitioned between ethyl acetate (50 mL) andwater (50 mL). The layers were separated and the organic phase waswashed with 5% aqueous HCl (25 mL), saturated aqueous NaHCO₃ (25 mL) andwater (25 mL), dried (MgSO₄) and concentrated under reduced pressure toafford the indanamide as a colourless solid (160 mg, 72%) which was usedwithout further purification.

¹H NMR (CDCl₃): 7.39–7.09 ppm (12H, m, 10 Ar and 2 NH); 6.99 (2H, s,Ar); 5.38 (1H, br s, CHAr); 5.01 (2H, s, CH ₂Ph); 4.81 (1H, m, NH); 4.19(2H, s, CH ₂NHBOC); 2.85–2.68 (4H, m, indane C(1)H₂ and C(3)H₂);2.04–1.88 (2H, m, indane C(2)H₂); 1.39 (9H, s, ^(t)Bu).

3-(N-BOC-Aminomethyl)benzoyl-D/L-4-(N-BOC-aminomethyl)-phenylglycineindan-5-amide

10% Palladium on carbon (50 mg), was added to a solution of theindanamide (160 mg, 0.3 mmol) in ethanol (20 mL) and the suspension wasstirred under a hydrogen atmosphere overnight The mixture was filteredand the filter was washed with ethanol (20 ml). The combined filtrateswere concentrated under reduced pressure to afford the amine as acolourless solid (107 mg, 90%) which was carried forward without furtherpurification.

A solution of the amine (107 mg, 0.27 mmol) in dimethylformamide (15 mL)was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (52 mg, 0.27 mmol), 1-hydroxy-7-azabenzotriazole (37 mg,0.27 mmol), N-BOC-3-(aminomethyl)benzoic acid (68 mg, 0.27 mmol) and4-(N,N-dimethylamino)pyridine (5 mg) and stirred overnight at roomtemperature. The solution was partitioned between ethyl acetate (25 mL)and water (25 mL) and the organic phase was separated and washed with 5%aqueous HCl (25 mL), saturated aqueous NaHCO₃ (25 mL) and water (25 mL)before being dried (MgSO₄) and concentrated under reduced pressure toafford a yellow solid. The residue was purified by flash chromatographyon silica gel (ethyl acetate/hexane 1:1) to give the diprotectedbis-amide as a colourless solid (103 mg, 61%).

¹H NMR (CDCl₃): 9.25 ppm (1H, s, NH); 7.94 (1H, d, J=7.2 Hz, Ar); 7.62(2H, s, Ar); 7.43–7.24 (5H, m, 4 Ar, NH); 7.05 (3H, d, J=7.2 Hz, Ar);6.94 (1H, d, J=7.2 Hz, Ar); 6.14 (1H, d, J=7.2 Hz, CH); 5.07 (1H, m,NH); 4.99 (1H, m, NH); 4.16 (2H, s, CH ₂NHBOC); 4.10 (2H, s, CH ₂NHBOC);2.77–2.61 (4H, m, indane C(1)H₂ and C(3)H₂); 1.98–1.87 (2H, m, indaneC(2)H₂); 1.35 (9H, s, ^(t)Bu).

3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine indan-5-amidebis(trifluoroacetate) salt

A solution of the diprotected bis-amide (103 mg, 0.16 mmol) indichloromethane (5 mL) was stirred at room temperature andtrifluoroacetic acid (3 mL) was added. Stirring was continued for afurther hour before the solvents were removed under reduced pressure toafford the bis(trifluoroacetate) salt as a colourless solid (92 mg,88%).

¹H NMR (d₄ MeOH): 7.90 ppm (1H, s, Ar); 7.84 (1H, s, Ar); 7.65–7.54 (4H,m, Ar); 7.49–7.32 (3H, m, Ar); 7.12 (1H, d, J=7.2 Hz, Ar); 7.02 (1H, d,J=7.2 Hz, Ar); 5.78 (1H, s, CHAr); 4.08 (2H, s, CH ₂NH₂); 4.01 (2H, s,CH ₂NH₂); 2.79–2.70 (4H, m, indane C(1)H₂ and C(3)H₂); 2.03–1.90 (2H, m,indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=3.13 minutes.

LCMS (Luna 2, Gradient 4): rt=1.45 minutes, 429 (MH)⁺.

Examples 62–64 were prepared in a similar fashion to Example 61, usingthe specified amine in place of 5-aminoindane.

Example 62 3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine1-aminoacetyl-2,3-dihydroindol-6-amide tris(trifluoroacetate salt)

Prepared from 6-amino-1-(N-BOC-aminoacetyl)-2,3-dihydroindole.

¹H NMR (d₄ MeOH): 8.23 ppm (1H, s, Ar); 7.84–7.74 (2H, m, Ar); 7.56–7.30(6H, m, Ar); 7.17 (1H, d, J=7.2 Hz, Ar); 7.02 (1H, d, J=7.2 Hz, Ar);5.68 (1H, s, CHAr); 4.02 (2H, s, CH ₂NH₂); 3.99–3.79 (6H, m, CH ₂NH₂,dihydroindole C(2)H₂, CH ₂NH₂ glycine); 3.06–2.97 (2H, m, dihydroindoleC(3)H₂).

HPLC (Luna 2, Gradient 1): rt=2.13 minutes.

LCMS (Luna 2, Gradient 4): rt=0.51 minutes, 487 (MH)⁺.

Example 63 3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine1-acetyl-2,3-dihydroindole bis(trifluoroacetate) salt

Prepared from 1-acetyl-6-amino-2,3-dihydroindole.

¹H NMR (d₄ MeOH): 8.21 ppm (1H, s, Ar); 7.97–7.86 (2H, m, Ar); 7.72–7.43(6H, m, Ar); 7.32 (1H, d, J=7.2 Hz, Ar); 7.12 (1H, d, J=7.2 Hz, Ar);5.81 (1H, s, CHAr); 4.17 (1H, s, CH ₂NH₂); 4.15–4.04 (4H, m, CH ₂NH₂,dihydroindole C(2)H₂); 3.19–3.07 (2H, m, dihydroindole C(3)H₂); 2.20(3H, s, NCOCH₃).

HPLC (Luna 2, Gradient 1): rt=2.72 minutes.

LCMS (Luna 2, Gradient 4): rt=1.18 minutes, 472 (MH)⁺.

Example 64 3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine4-(isopropyl)phenylamide bis(trifluoroacetate salt)

Prepared from 4-isopropylaniline.

¹H NMR (d₄ MeOH): 8.01–7.92 ppm (2H, m, Ar); 7.75–7.43 (8H, m, Ar); 7.18(2H, d, J=9.6 Hz, Ar); 5.87 (1H, s, CHAr); 4.21 (2H, s, CH ₂NH₂); 4.14(2H, s, CH ₂NH₂); 2.96–2.81 (1H, m, CH(CH₃)₂); 1.24 (6H, d, J=7 Hz,CH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=3.39 minutes.

LCMS (Luna 2, Gradient 4): rt=1.59 minutes, 431 (MH)⁺.

Examples 65–68 were prepared in a similar manner to Example 61 exceptthat the indicated protected amino acid was used in the place ofD/L-4-(N-BOC-aminomethyl)-α-(N-benzyloxycarbonyl)phenylglycine.

Example 65 3-(Aminomethyl)benzoyl-D-cyclohexylglycine indan-5-amidetrifluoroacetate salt

Prepared from N-BOC-D-cyclohexylglycine.

¹H NMR (d₄ MeOH): 7.88–7.02 ppm (7H, m, Ar); 4.43 (1H, d, J=9 Hz,CH(cHex)); 4.04 (2H, s, CH ₂NH₂); 2.78–2.68 (4H, m, indane C(1)H₂ andC(3)H₂); 2.04–1.82 (4H, m, indane C(2)H₂, cHex CH₂); 1.77–1.56 (4H, m,2× cHex CH₂); 1.36–0.95 (5H, m, 2× cHex CH₂ and CH).

HPLC (Luna 2, Gradient 1): rt=4.27 minutes.

LCMS (Luna 2, Gradient 4): rt=2.21 minutes, 406 (MH)⁺.

Example 66 3-(Aminomethyl)benzoyl-D/L-1-naphthylglycine indan-5-amidetrifluoroacetate salt

Prepared from N-BOC-D/L-1-naphthylglycine.

¹H NMR (d₄ MeOH): 8.25 ppm (1H, d, J=7.2 Hz, Ar); 8.04–7.84 (4H, m Ar);7.75–7.44 (7H, m, Ar); 7.33 (1H, d, J=7.25 Hz, Ar); 7.16 (1H, d, J=7.25Hz, Ar); 6.72 (1H, s, CHAr); 4.15 (2H, s, CH ₂NH₂); 2.94–2.78 (4H, m,indane C(1)H₂C(3)H₂); 2.17–1.98 (2H, m, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.37 minutes.

LCMS (Luna 2, Gradient 4): rt=2.37 minutes, 450 (MH)⁺.

Example 67 3-(Aminomethyl)benzoyl-D/L-(4-phenyl)phenylglycineindan-5-amide trifluoroacetate salt

Prepared from N-Fmoc-D/L-(4-phenyl)phenylglycine.

¹H NMR (d₄ MeOH): 7.94–7.83 ppm (2H, m, Ar); 7.64–7.15 (13H, m, Ar);7.02 (1H, d, J=7.2 Hz, Ar); 5.80 (1H, s, CH); 4.08 (2H, s, CH ₂NH₂);2.81–2.77 (4H, m, indane C(1)H₂ and C(3)H₂); 2.01–1.88 (2H, m, indaneC(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.87 minutes.

LCMS (Luna 2, Gradient 4): rt=2.56 minutes, 476 (MH)⁺.

Example 68 3-(Aminomethyl)benzoyl-D-(4-aminophenyl)glycine indan-5-amidebis(trifluoroacetate) salt

Prepared from N-BOC-D-(4-Benzyloxycarbonylaminophenyl)-glycine (preparedas described below).

D-(4-Hydroxyphenyl)glycine methyl ester hydrochloride

D-4-Hydroxyphenylglycine (12.5 g, 74.8 mmol) and dry methanol (24 mL)were stirred in a dry 250 mL three necked round bottom flask, equippedwith a low temperature thermometer. The mixture was stirred undernitrogen and cooled to an internal temperature of below −20° C. Using asyringe, thionyl chloride (6 mL, 9,78 g, 82.2 mmol) was added dropwiseto the cooled mixture over a period of 10 minutes at such a rate thatthe internal temperature did not exceed −20° C. Once the addition wascomplete the mixture was allowed to warm to room temperature and stirredovernight. Dry ether (150 mL) was added and the white precipitate thatformed was collected by suction filtration, washed with a little moreether and dried (15.5 g, 95%).

N-BOC-D-(4-Hydroxyphenyl)glycine methyl ester

Di-t-butyl dicarbonate (15.9 g, 72.8 mmol) was added to a stirredmixture of D-4-hydroxyphenylglycine methyl ester hydrochloride (14 g,64.3 mmol) and NaHCO₃ (11.7 g, 0.14 mol) in tetrahydrofuran (150 mL) andwater (50 mL), in one portion. The mixture was stirred rapidly for 4 h.Hexane (75 mL) was added and the organic layer separated and washed withsaturated aqueous NaHCO₃ (20 mL) and brine (20 mL) and dried (MgSO₄).Evaporation of the solvent afforded the N-BOC-protected amine (19.7 g,96%).

N-BOC-D-(4-Trifluoromethylsulphonyloxyphenyl)glycine methyl ester

2,6-Lutidine (9.44 ml, 8.68 g, 81.0 mmol) and 4-dimethylaminopyridine(1.65 g, 13.5 mmol) were added to a stirred solution ofN-BOC-D-(4-hydroxyphenyl)glycine methyl ester (19 g, 67.5 mmol) indichloromethane (400 mL) and the mixture cooled in an ice bath.Trifluoromethananesulphonic anhydride (13.7 mL, 23.0 g, 81.4 mmol) wasadded over a period of five minutes and then the mixture was allowed towarm to room temperature over four hours. The solution was washed withwater (2×150 mL), 1N HCl (2×150 mL) and saturated aqueous NaHCO₃ (150mL) and dried (MgSO₄). Evaporation of the solvent afforded an oil whichwas purified by flash chromatography on silica gel(hexane/dichloromethane 1:1 and then neat dichloromethane) affording thetriflate as a white solid (19 g, 77%).

N-BOC-D-(4-benzyloxycarbonylphenyl)glycine methyl ester

N-BOC-D-(4-trifluoromethylsulphonyloxyphenyl)glycine methyl ester (27.6g, 77.0 mmol), benzyl alcohol (32.6 mL, 34.1 g, 315 mmol), palladium(II) acetate (255 mg, 1.13 mmol), bis-1,3-diphenylphosphinylpropane (448mg, 1.09 mmol) and triethylamine (10.2 mL, 7.40 g, 73.2 mmol) indimethylformamide (72 mL) were placed in a Parr reactor and the reactorassembled. The vessel was pressurised to ˜10 psi with nitrogen and thegas released (repeated five times to remove all oxygen from the system).Carbon monoxide gas was then carefully introduced to ˜20 psi andreleased three times.

Carbon monoxide was then added to ˜100 psi and the stirrer started. Thevessel was slowly heated to 65° C. internal temperature and thenstirred, monitoring by tlc. When complete (after ˜18 hours) the reactionwas cooled to 30° C., the gas released and the vessel flushed five timeswith nitrogen as before. The reaction mixture was partitioned betweenethyl acetate (250 mL) and water (100 mL) and the organic layer washedwith 1M hydrochloric acid (30 mL) and saturated aqueous NaHCO₃ (30 mL)and dried (MgSO₄) and evaporated. Purification of the resulting oil bycolumn chromatography (ethyl acetate/hexane; 1:4) gave the benzyl ester(18.7 g, 70%).

N-BOC-D-(4-hydroxycarbonylphenyl)glycine methyl ester

10% Palladium on carbon (100 mg) was added to a solution of the benzylester (500 mg, 1.25 mmol) in ethanol (15 mL) and the suspension wasstirred under a hydrogen atmosphere overnight. The mixture was filteredand the residue was washed with ethanol (20 mL) and the combined organicsolvents were evaporated under reduced pressure to afford the acid as acolourless solid (363 mg, 94%).

¹H NMR (CDCl₃): 8.08 ppm (2H, br s, Ar); 7.49 (2H, d, J=7.2 Hz, Ar);5.87 (1H, d, J=9 Hz, NHCH); 3.73 (3H, s, OCH₃); 1.41 (9H, s, ^(t)Bu).

N-BOC-D-(4-Benzyloxycarbonylaminophenyl)glycine methyl ester

The acid (218 mg, 0.7 mmol) in tetrahydrofuran (20 mL) was treated withtriethylamine (108 μl, 0.78 mmol) and diphenylphosphonic azide (161 μl,0.78 mmol) and stirred at room temperature for 1.5 hours. Benzyl alcohol(116 μl, 1.12 mmol) was then added and the mixture was heated at refluxfor 18 hours. The solvent was evaporated under reduced pressure and theresidue was purified by flash chromatography (ethyl acetate/hexane, 1:1)to give the N-benzyloxycarbonylaniline as a brown solid (87 mg, 30%).

¹H NMR (CDCl₃): 7.35–7.23 ppm (7H, m, Ar); 7.16 (2H, d, J=9 Hz, Ar);7.06 (1H, s, NH); 5.53 (1H, d, J=9 Hz, CHAr); 5.18 (1H, d, J=9 Hz, NH);5.10 (2H, s, CH₂Ph); 3.59 (3H, s, OCH₃); 1.31 (9H, s, ^(t)Bu).

N-BOC-D-(4-Benzyloxycarbonylaminophenyl)glycine

A solution of the ester (87 mg, 0.21 mmol) in tetrahydrofuran (5 mL) wastreated with 1 M LiOH (0.84 ml, 0.84 mmol) and heated at reflux for fourhours. The solvent was removed under reduced pressure and the residuewas diluted with water (10 mL). The aqueous solution was acidified to pH4 using 5% aqueous HCl and extracted with ethyl acetate (3×10 mL). Thecombined extracts were dried (MgSO₄) and evaporated under reducedpressure to afford the crude acid (80 mg, 95%) as a colourless solidwhich was carried forward without further purification.

3-(Aminomethyl)benzoyl-D-(4-aminophenyl)glycine indan-5-amidebis(trifluoroacetate) salt

¹H NMR (d₄ MeOH): 7.92–7.80 ppm (2H, m, Ar); 7.69 (2H, d, J=7.3 Hz, Ar);7.60–7.40 (2H, m, Ar); 7.34 (3H, d, J=12 Hz, Ar); 7.15 (1H, d, J=7.2 Hz,Ar); 7.02 (1H, d, J=7.2 Hz, Ar); 5.79 (1H, s, CHAr); 4.07 (2H, s, CH₂NH₂); 2.80–2.69 (4H, m, indane C(1)H₂ and C(3)H₂); 2.01–1.88 (2H, m,indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=3.17 minutes.

LCMS (Luna 2, Gradient 4): rt=1.59 minutes, 415 (MH)⁺.

Example 69 3-(Aminomethyl)benzoyl-D/L-piperidin-4-ylglycineindan-5-amide bis(trifluoroacetate) salt(N-BOC-Piperidin-4-ylidene)-(N-benzyloxycarbonyl)glycine methyl ester

N-BOC-4-Piperidone (2.0 g, 10 mmol),N-(benzyloxy-carbonyl)-α-phosphonoglycine trimethyl ester (3.64 g, 2.20mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.57 mL, 2.10 mmol) werestirred in acetonitrile overnight. The solvent was removed and theresidue taken up in ethyl acetate (50 mL) and washed with water (2×10mL), dried (MgSO₄) and evaporated under reduced pressure. The residualoil was purified by chromatography on silica gel (ethyl acetate/hexane,40%/60%) to afford the unsaturated ester (3.63 g, 90%).

¹H NMR (CDCl₃): 7.36 ppm (5H, br s, Ph); 6.05 (1H, br s, NH); 5.12 (2H,s, CH ₂Ph); 3.73 (3H, br s, OMe); 3.50 (4H, br s, piperidine C(2)H₂ andC(6)H₂); 2.86 (2H, br s, piperidine C(3) H₂ or C(5)H₂); 2.45–2.36 (2H,m, piperidine C(3)H₂ or C(5) H₂); 1.47 (9H, s, ^(t)Bu).

(N-BOC-Piperidin-4-ylidene)-(N-benzyloxycarbonyl)glycine

A solution of the methyl ester (391 mg, 1 mmol) in tetrahydrofuran (10mL) was treated with 1 M LiOH (2 mL, 2 mmol) and heated at reflux for 4hours. The solvent was removed under reduced pressure and the residuediluted with water (20 mL). The aqueous solution was acidified to pH 4with 5% aqueous HCl and extracted with ethyl acetate (3×20 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure to afford the acid as a brown solid (305 mg, 78%) whichwas carried forward without further purification.

(N-BOC-Piperidin-4-ylidene)-(N-benzyloxycarbonyl)glycine indan-5-amide

A solution of the acid (253 mg, 0.65 mmol) in dimethylformamide (20 mL)was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (124 mg, 0.65 mmol), 1-hydroxy-7-azabenzotriazole (88 mg,0.65 mmol), 5-aminoindane (86 mg, 0.65 mmol) and4-(N,N-dimethylamino)pyridine (10 mg) and stirred overnight at roomtemperature. The solution was partitioned between ethyl acetate (30 mL)and water (30 mL), separated, and the organic phase was washed with 5%aqueous HCl (30 mL), saturated aqueous NaHCO₃ (30 mL) and water (30 mL),dried (MgSO₄) and concentrated under reduced pressure to afford acolourless solid. The crude product was purified by flash chromatography(ethyl acetate/hexane 1:1) to afford the indanamide as a colourlesssolid (215 mg, 65%).

¹H NMR (CDCl₃): 8.31 (1H, br s, NH); 7.43 (9H, m, 8 Ar, NH); 5.01 (2H,s, CH ₂Ph); 3.34 (4H, br s, piperidine C(2)H₂ and C(6)H₂); 2.83–2.71(4H, m, indane C(1)H₂ and C(3)H₂); 2.54 (2H, br s, piperidine C(3)H₂ orC(5)H₂); 2.23–2.14 (2H, m, piperidine C(3)H₂ or C(5)H₂); 2.05–1.92 (2H,m, indane C(2)H₂); 1.38 (9H, s, ^(t)Bu).

D/L-(N-BOC-Piperidin-4-yl)glycine indan-5-amide

10% Palladium on carbon (50 mg) was added to a solution of the alkene(215 mg, 0.43 mmol) in ethanol (20 mL) and the suspension was stirredunder a hydrogen atmosphere overnight. The mixture was filtered and thefiltrand was washed with ethanol (20 ml) before the combined solventswere concentrated under reduced pressure to afford the deprotectedsaturated amine as a colourless oil (97 mg, 60%). The crude amine wascarried forward without further purification.

The remaining steps of the synthesis are identical to those of Example61.

3-(Aminomethyl)benzoyl-D/L-piperidin-4-ylglycine indan-5-amidebis(trifluoroacetate) salt

¹H NMR (d₄ MeOH): 8.04–7.92 ppm (2H, m, Ar); 7.73–7.55 (2H, m, Ar); 7.49(1H, s, Ar); 7.32 (1H, d, J=7.2 Hz, Ar); 7.18 (1H, d, J=7.2 Hz, Ar);4.68 (1H, d, J=9 Hz, CH(Pip)); 4.21 (2H, s, CH ₂NH₂); 3.54–3.40 (2H, m,piperidine C(2)H and C(6)H); 3.13–2.96 (2H, m, piperidine C(2)H andC(6)H); 2.94–2.81 (4H, m, indane C(1)H₂ and C(3)H₂); 2.41–2.23 (1H, m,piperidine C(4)H); 2.20–1.95 (4H, m, indane C(2)H₂, piperidine C(3)H andC(4)H); 1.84–1.60 (2H, m, piperidine C(3)H and C(4)H).

HPLC (Luna 2, Gradient 1): rt=3.08 minutes.

LCMS (Luna 2, Gradient 4): rt=1.27 minutes, 407 (MH)⁺.

Example 70 2-Amino-5-(aminomethyl)benzoyl-D-phenylglycineindan-5-ylamide bis(trifluoroacetate) salt 2-Amino-5-cyanobenzoic acid

A solution of 2-amino-5-bromobenzoic acid (6.9 g, 31.9 mmol) inN-methyl-2-pyrrolidinone (100 mL) was treated with copper cyanide (4.14g, 46 mmol) and the mixture was heated at 190° C. for 4.5 hours beforebeing cooled to room temperature and allowed to stand overnight. Themixture was diluted with water (500 mL), acidified with 6N aqueous HCl(100 mL) and extracted with ethyl acetate (6×40 mL). The organicextracts were dried (MgSO₄) and concentrated under reduced pressure toyield the crude nitrile (4.35 g, 84%).

2-Amino-5-cyanobenzoyl-D-phenylglycine methyl ester

A solution of 2-amino-5-cyanobenzoic acid (1.0 g, 6.17 mmol) indimethylformamide (50 mL) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.18 g,6.17 mmol) and 1-hydroxy-7-azabenzotriazole (0.84 g, 6.17 mmol). Afterstirring for 10 minutes, D-phenylglycine methyl ester (1.24 g, 6.17mmol) was added and the resulting solution was stirred overnight at roomtemperature. The mixture was partitioned between ethyl acetate (50 mL)and water (50 mL) and the organic solution was washed with saturatedaqueous citric acid (50 mL), saturated aqueous NaHCO₃ (50 mL) and water(50 mL), dried (MgSO₄) and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography (ethylacetate/hexane, 1:1) to yield 2-amino-5-cyanobenzoyl-D-phenylglycinemethyl ester (1.3 g, 68%).

LC/MS (Luna 2, Gradient 4): rt=3.28 minutes, 310 (MH)⁺.

2-(Di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycine methyl ester

A solution of 2-amino-5-cyanobenzoyl-D-phenylglycine methyl ester (800mg, 2.6 mmol) in dimethylformamide (20 mL) was treated with4-dimethylaminopyridine (30 mg; 0.3 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (500 mg; 2.6mmol) and di-t-butyldicarbonate (570 mg; 2.6 mmol). The mixture wasstirred overnight at room temperature and then partitioned between ethylacetate (25 mL) and water (25 mL). The organic extracts were dried(MgSO₄), concentrated under reduced pressure and the residue waspurified by flash column chromatography (ethyl acetate/hexane 3:7) toyield the bis-protected amine (150 mg, 11%).

2-(Di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycine

The ester (150 mg, 0.29 mmol) was dissolved in tetrahydrofuran (20 mL)and treated with 1 M lithium hydroxide (0.6 mL, 0.6 mmol). The mixturewas heated at reflux for 3 hours, cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with water(10 mL), acidified with 5% aqueous HCl (10 mL) and the product extractedinto ethyl acetate (25 mL). The organic extracts were then dried (MgSO₄)and concentrated under reduced pressure and the crude acid (110 mg, 75%)was carried forward without further purification.

2-(Di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycineindan-5-ylamide

A solution of the acid (110 mg, 0.20 mmol) in dimethylformamide (1.0 mL)was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (30 mg, 0.2 mmol) and 1-hydroxy-7-azabenzo-triazole (30mg, 0.2 mmol). After stirring for 10 minutes, 5-aminoindane (30 mg, 0.2mmol) was added and the resulting solution stirred overnight at roomtemperature. The mixture was partitioned between ethyl acetate (25 mL)and water (25 mL) and the organic solution was washed with saturatedaqueous citric acid (25 mL), saturated aqueous NaHCO₃ (25 mL) and water(25 ml), dried (MgSO₄) and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography (ethylacetate/hexane, 3:7) to yield2-(di-t-butoxycarbonyl)amino-5-cyanobenzoyl-D-phenylglycineindan-5-ylamide as an off-white solid (50 mg, 40%).

2-Amino-5-(aminomethyl)benzoyl-D-phenylglycine indan-5-ylamidebis(trifluoroacetate) salt

A solution of the nitrile (50 mg, 0.08 mmol) in methanol (10 mL) and 36%aqueous HCl (0.5 ml) was stirred over 10% palladium on carbon (20 mg)under a hydrogen atmosphere for 16 hours. The mixture was filtered andthe residue was washed with methanol (10 mL) before concentrating theextracts under reduced pressure.

The residue was dissolved in a mixture of trifluoroacetic acid (5 ml)and dichloromethane (5 ml) and stirred for one hour. The mixture wasconcentrated under reduced pressure and the residue purified bypreparative HPLC to afford2-amino-5-(aminomethyl)benzoyl-D-phenylglycine indan-5-ylamideditrifluoroacetate salt (2 mg, 6%).

¹H NMR (d₄ MeOH): 7.98–7.37 ppm (10H, m, Ar); 7.02 (1H, d, J=7.5 Hz,Ar); 6.03 (1H, s, CHPh); 3.92 (2H, s, CH ₂NH₂); 3.09 (4H, q, J=7.5 Hz,indane C(1)H₂ and C(3)H₂); 2.29 (2H, quintet, J=7.5 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.04 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.10 minutes, 398 (MH-NH₃)⁺.

Example 71 1-(2-Amino-5-(aminomethyl)benzoyl-D-phenylglycinyl)4-hydroxypiperidine dihydrochloride salt D-Phenylglycine4-hydroxypiperidinamide trifluoroacetate salt

A solution of 4-hydroxypiperidine (330 mg, 1.4 mmol) indimethylformamide (10 mL) was treated with2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(450 mg; 1.4 mmol) and N-ethyldiisopropylamine (0.74 mL, 4.2 mmol).After stirring for 10 minutes, N-butoxycarbonyl-D-phenylglycine (330 mg,1.4 mmol) was added and the resulting solution stirred overnight at roomtemperature. The mixture was partitioned between ethyl acetate (25 mL)and water (25 mL) and the organic solution was washed with saturatedaqueous citric acid (25 mL), saturated aqueous NaHCO3 (25 mL) and water(25 mL), dried (MgSO4) and concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid(5 mL) and stirred for one hour before the solvents were removed underreduced pressure, giving D-phenylglycine-4-hydroxypiperidinamide as itstrifluoracetate salt (150 mg, 43%).

LC/MS (Luna 2, Gradient 4): rt=2.64 min, 235 (MH)⁺.

2-amino-5-cyanobenzoyl-D-phenylglycine 4-hydroxypiperidinamide

A solution of 2-amino-5-cyanobenzoic acid (170 mg, 1.0 mmol) indimethylformamide (10 mL) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (210 mg, 1.1mmol) and 1-hydroxy-7-azabenzotriazole (150 mg, 1.1 mmol). Afterstirring for 10 minutes, D-phenylglycine 4-hydroxypiperidinamidetrifluoroacetate salt (250 mg; 1.1 mmol) was added and the resultingsolution stirred overnight at room temperature. The mixture waspartitioned between ethyl acetate (25 mL) and water (25 mL) and theorganic solution was washed with saturated aqueous citric acid (25 mL),saturated aqueous NaHCO₃ (25 mL) and water (25 mL), dried (MgSO₄) andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (ethyl acetate) to yield2-amino-5-cyanobenzoyl-D-phenylglycine 4-hydroxypiperidinamide (90 mg,23%).

1-(2-amino-5-(aminomethyl)benzoyl-D-phenylglycinyl 4-hydroxypiperidinedihydrochloride salt

A solution of the nitrile in methanol (10 mL) and 36% hydrochloric acid(0.5 mL) was stirred over 10% palladium on carbon (20 mg) under anatmosphere of hydrogen for 16 hours. The mixture was filtered and theresidue washed with methanol (10 mL) before concentrating the filtrateunder reduced pressure. Purification by preparative HPLC afforded2-amino-5-(aminomethyl)benzoyl-D-phenylglycine 4-hydroxy-piperidinamidedihydrochloride salt (30 mg, 33%).

¹H NMR (d₄ MeOH): 7.84 ppm (1H, s, Ar); 7.61–7.17 (7H, m, Ar); 6.85 (1H,d, J=8 Hz, Ar); 6.12 (1H, s, CHPh); 4.26 (1H, m, piperidine C(4)H); 3.99(2H, s, CH ₂NH₂); 3.79 (2H, m, piperidine C(2)H and C(6)H); 3.42–3.08(2H, m, piperidine C(2)H and C(6)H); 1.86–0.72 (4H, m, piperidine C(3)H₂and C(5)H₂).

HPLC (Luna 2, Gradient 1): rt=2.49 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.35 minutes, 366 (MH-NH₃)⁺.

Example 72 3-(Aminomethyl)benzoyl-D-phenylglycine1-(2-hydroxyphenyl)acetyl-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared in a similar manner to Example 35, using(2-hydroxyphenyl)acetic acid.

¹H NMR (CD₃CN): 8.91 ppm (1H, s, OH), 8.30 (1H, s, NH), 7.94 (2H, br s,Ar), 7.73 (1H, d, J=10 Hz, Ar), 7.54–7.06 (12H, m, Ar & NH), 7.01 (1H,d, J=8 Hz, Ar), 6.74 (2H, m, Ar), 5.61 (1H, d, J=8 Hz, ArCH), 4.21 (2H,t, J=8 Hz, dihydroindole C(2)H₂), 4.10 (2H, s, ArCH ₂N), 3.73 (2H, s,ArCH ₂CO), 3.10 (2H, d, J=8 Hz, dihydroindole C(3)H₂).

HPLC (Symmetry, Gradient 2): rt=6.24 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.10 minutes, 535 (MH)⁺.

Example 73 3-(Aminomethyl)benzoyl-D-phenylglycine1-(3-hydroxyphenyl)acetyl-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared in a similar manner to Example 35, using(3-hydroxyphenyl)acetic acid.

¹H NMR (d₄ MeOH): 8.21 ppm (1H, s, Ar), 7.71 (2H, br s, Ar), 7.50–7.16(8H, m, Ar), 7.05–6.95 (2H, m, Ar), 6.64–6.50 (3H, m, Ar), 5.62 (1H, s,ArCH), 4.09 (2H, s, ArCH ₂N), 4.04 (2H, t, J=8 Hz, dihydroindoleC(2)H₂), 3.68 (2H, s, ArCH ₂CO), 2.91 (2H, d, J=8 Hz, dihydroindoleC(3)H₂).

HPLC (Symmetry, Gradient 2): rt=5.95 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 535 (MH⁺).

Example 74 3-(Aminomethyl)benzoyl-D-phenylglycine1-(4-hydroxyphenyl)acetyl-2,3-dihydroindol-6-amide trifluoroacetate salt

Prepared in a similar manner to Example 35, using (4hydroxyphenyl)aceticacid.

¹H NMR (d₄ MeOH): 8.32 ppm (1H, s, Ar), 8.04 (2H, br s, Ar), 7.66–7.34(8H, m, Ar), 7.22–7.11 (3H, m, Ar), 6.80 (2H, d, J=10 Hz, Ar), 5.85 (1H,s, ArCH), 4.21 (2H, s, ArCH ₂N), 4.15 (2H, t, J=8 Hz, dihydroindoleC(2)H₂), 3.81 (2H, s, ArCH ₂CO), 3.20 (2H, d, J=8 Hz, dihydroindoleC(3)H₂).

HPLC (Symmetry, Gradient 2): rt=5.97 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.02 minutes, 535 (MH⁺).

Example 75 3-(Aminomethyl)benzoyl-D-phenylglycine1-benzyl-3-acetylindol-5-amide trifluoroacetate salt

Prepared in a similar fashion to Example 1, starting from3-acetyl-5-amino-1-benzylindole, which was prepared as described below.

3-Acetyl-5-nitroindole and 3-acetyl-7-nitroindole

Prepared by the method described by Ottoni, Cruz and Kramer inTetrahedron Letters, 40, 1999, 1117–1120, as a mixture of isomers.

3-Acetyl-1-benzyl-5-nitroindole and 3-acetyl-1-benzyl-7-nitroindole

Potassium carbonate (940 mg, 6.8 mmol) was added to a stirred solutionof the above indoles (695 mg, 3.4 mmol) in dimethylformamide (30 mL).Benzyl bromide (0.61 mL, 5.1 mmol) was then added dropwise and themixture left to stir over the weekend. The dimethylformamide was removedunder reduced pressure and the residue partitioned between ethyl acetate(30 mL) and water (20 mL). The ethyl acetate layer was dried (MgSO₄) andevaporated to give the benzylamines as a golden oil.

3-Acetyl-5-amino-1-benzylindole and 3-acetyl-7-amino-1-benzylindole

A mixture of the indoles (1.0 g, 3.4 mmol), tin(II) chloride dihydrate(3.48 g, 15.4 mmol) and ethanol (20 mL) was heated at reflux, under anatmosphere of nitrogen, for 3 hours. The mixture was cooled and thesolvent evaporated to give a brown oil. To this was added water (50 mL),which was then made basic with 1 N aqueous sodium hydroxide. The aqueoussolution was then extracted with ethyl acetate (2×30 mL). The wholebiphasic mixture was filtered through celite to remove tin salts,separated and the organic solvent dried (MgSO₄). The solvent was removedunder reduced pressure to give a brown oil which was purified by flashchromatography on silica gel (hexane/ethyl acetate; 3:1) to afford, inorder of elution,

3-acetyl-7-amino-1-benzylindole

¹H NMR (CDCl₃): 7.67 ppm (1H, s, indole C(2)H); 7.39–7.13 (3H, m, Ph);7.15 (2H, m, Ph); 7.05 (1H, t, J=6 Hz, indole C(5)H); 6.57 (1H, d, J=6.5Hz, indole C(4)H); 6.41 (1H, d, J=6 Hz, indole C(6)H); 5.95 (2H, br s,NH₂); 5.27 (2H, s, PhCH ₂); 2.50 (3H, s, CH₃)

and 3-acetyl-5-amino-1-benzylindole

¹H NMR (CDCl₃): 8.08 ppm (1H, d, J=6 Hz, indole C(7)H); 7.50 (1H, s,indole C(2)H); 7.31–7.22 (3H, m, Ph); 7.05 (2H, m, Ph); 6.63 (1H, dd,J=6, 2 Hz, indole C(6)H); 6.45 (1H, s, indole 4-H); 5.25 (2H, s, PhCH₂); 3.62 (2H, br s, NH₂); 2.5 (3H, s, CH₃).

3-(Aminomethyl)benzoyl-D-phenylglycine 1-benzyl-3-acetylindol-5-amidetrifluoroacetate salt

¹H NMR (d₄ MeOH): 8.28 ppm (1H, s, Ar); 8.20 (1H, d, J=5 Hz, Ar); 7.97(3H, m, Ar); 7.71–7.56 (4H, m, Ar); 7.47–7.19 (9H, m, Ar); 5.85 (1H, s,CHPh); 5.45 (2H, s, CH ₂Ph); 4.21 (2H, CH ₂NH₂); 2.53 (3H, s, CH₃).

HPLC (Luna 2, Gradient 1): rt=4.15 minutes.

HPLC (Symmetry, Gradient 2): rt=6.77 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.48 minutes, 531 (MH)⁺.

Example 76 3-(Aminomethyl)benzoyl-D-phenylglycine1-benzyl-3-acetylindol-7-amide trifluoroacetate salt

Prepared in a similar fashion to Example 1, starting from3-acetyl-7-amino-1-benzylindole, which was prepared as described above.

¹H NMR (d₄ MeOH): 8.46 ppm (1H, s, Ar); 8.34 (1H, d, J=6 Hz, Ar);8.11–7.95 (3H, m, Ar); 7.75–7.48 (4H, m, Ar); 7.46–7.12 (9H, m, Ar);5.85 (1H, s, CHPh); 5.48 (2H, s, CH ₂Ph); 4.21 (2H, s, CH ₂NH₂); 2.62(3H, s, CH ₃).

HPLC (Luna 2, Gradient 1): rt=4.58 minutes.

HPLC (Symmetry, Gradient 2): rt=6.80 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.80 minutes, 531 (MH)⁺.

Example 77 3-(Aminomethyl)benzoyl-D-(4-hydroxyphenyl)glycineindan-5-amide trifluoroacetate salt

Prepared in a similar fashion to Example 61, using(4-hydroxyphenyl)glycine and protecting as appropriate.

¹H NMR (d₄ MeOH): 8.00 ppm (2H, s, Ar); 7.72–7.55 (2H, m, Ar); 7.47 (3H,t, J=8.6 Hz, Ar); 7.31 (1H, d, J=7.5 Hz, Ar); 7.18 (1H, d, J=8 Hz, Ar);6.86 (2H, d, J=8.6 Hz, Ar); 5.75 (1H, s, CHPh); 4.23 (2H, s, CH ₂NH₂);2.94 (4H, m, indane C(1)H ₂ and C(3)H ₂); 2.12 (2H, m, indane C(2)H ₂).

HPLC (Luna 2, Gradient 1): rt=3.78 minutes.

HPLC (Symmetry, Gradient 2): rt=5.80 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 416 (MH)⁺.

Example 783-(Aminomethyl)benzoyl-D/L-2-(N-formylamino)thiazol-4-yl]glycine5-indanamide trifluoroacetate salt

Prepared using the same method as described for Example 61 fromD/L-α-(N-^(t)butyloxycarbonyl)-[2-(N-formylamino)thiazol-4-yl]glycine(synthesised as described below).

Ethyl α-azido-[2-(N-formylamino)thiazol-4-yl]acetate

A solution of ethyl[2-(N-formylamino)thiazol-4-yl]acetate (1 g, 0.0047mol) in THF (10 mL) was stirred under argon at −78° C. and potassiumbis(trimethylsilyl)amide (2.8 g, 0.014 mol) in THF (10 mL) was added.After stirring for 30 minutes, 2,4,6-triisopropylbenzenesulfonyl azide(3.6 g, 0.012 mol) was added as a solid in one portion. After 5 minutes,acetic acid (1.4 mL, 0.018 mol) was added and the mixture warmed to roomtemperature. The reaction mixture was then partitioned between ethylacetate (100 mL) and water (100 mL), separated and the organic layerdried (MgSO₄). Evaporation of the solvent and purification of theresidue by silica gel chromotography afforded the azide (0.95 g, 80%).

¹H NMR (CDCl₃): 8.78 ppm (1H, s, NHCHO); 6.98 (1H, s, C(5)H); 5.95 (1H,s, CHN₃); 4.18 (2H, m, CH ₂CH₃); 1.20 (3H, m, CH₂CH ₃).

Ethylα-(N-^(t)butyloxycarbonylamino)-[2-(N-formylamino)thiazol-4-yl]acetate

Di-^(t)butyl dicarbonate (0.9 g, 0.004 mol) and 5% palladium on carbon(catalytic amount) were added to a solution of the azide (0.95 g, 0.0037mol) in methanol (25 mL). The mixture was stirred at room temperatureunder an atmosphere of hydrogen for 8 hours. After this time the mixturewas filtered through celite, washing through with methanol (25 mL).Evaporation of the solvent and purification of the residue by silica gelchromatography afforded the ^(t)butyloxycarbonyl amine as a pale oilysolid (1.1 g, 90%).

¹H NMR (CDCl₃): 8.53 ppm (1H, s, NHCHO); 6.89 (1H, s, C(5)H); 6.18 (1H,d, J=8 Hz, NHBoc); 5.38 (1H, d, J=8 Hz, CHN); 4.06 (2H, m, CH ₂CH₃);1.28 (9H, s, ^(t)Bu); 1.12 (3H, m, CH₂CH ₃).

D/L-α-N-^(t)butyloxycarbonyl-[2-(N-formylamino)thiazol-4-yl]glycine

A solution of the ester (1.1 g, 0.0031 g) in THF (25 mL) was treatedwith 1 M aqueous LiOH (5 ml, 0.005 mol) and heated at reflux for 1 hour.The solvent was removed under reduced pressure and the residue dilutedwith water (100 mL). The pH was reduced to 2 using 5% aqueous HCl andthe aqueous phase was extracted with ethyl acetate (3×50 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated underreduced pressure to afford the acid as a white solid (0.8 g, 84%).

¹H NMR (d₄ MeOH): 8.38 ppm (1H, s, NHCHO); 7.01 (1H, s, C(5)H); 5.21(1H, s, CHN); 1.39 (9H, s, ^(t)Bu).

3-(Aminomethyl)benzoyl-D/L-[2-(formylamino)thiazol-4-yl]glycine5-indanamide trifluoroacetate salt

¹H NMR (d₄ MeOH): 10.10 ppm (1H, s, NHCHO); 8.80 (1H, d, J=8 Hz, NH);8.48 (1H, s, NHCHO); 7.97 (2H, br s, Ar); 7.58 (2H, m, Ar); 7.42 (1H, s,aminothiazole C(5)H); 7.37 (1H, d, J=7 Hz, indane C(6)H); 7.18 (1H, s,indane C(4)H); 7.10 (1H, d, J=7 Hz, indane C(7)H); 5.92 (1H, m, CHAr);4.18 (2H, s, CH ₂NH₂); 2.83 (4H, m, indane C(1)H₂ and C(3)H₂); 2.02 (2H,m, indane C(2)H₂)

HPLC (Luna 2, gradient 1): rt=3.71 minutes.

LC/MS (Luna 2, gradient 4): rt=2.05 minutes; 450 (MH)⁺.

Example 793-(Aminomethyl)benzoyl-D/L-2-aminothiazol-4-ylglycine-5-indanamidebis(hydrochloride) salt

Prepared fromD/L-α-N-^(t)butyloxycarbonyl-[2-(N-formylamino)thiazol-4-yl]glycine andsynthesised using the method of Example 80 except that the finaldeprotection was effected using 3 M aqueous HCl in THF, in order toremove both the ^(t)butyloxycarbonyl and formyl protecting groups.

¹H NMR (d₄ MeOH): 7.87 ppm (2H, m, Ar); 7.51 (1H, m, Ar); 7.48 (1H, t,J=7 Hz, (aminomethyl)benzoyl C(3)H); 7.40 (1H, s, aminothiazole C(5)H);7.20 (1H, d, J=8 Hz, indane C(6)H); 7.05 (1H, d, J=8 Hz, indane C(7)H);6.73 (1H, s, indane C(4)H); 5.78 (1H, s, CHAr); 4.12 (2H, s, CH ₂NH₂);2.79 (4H, m, indane C(1)H₂ and C(3)H₂); 2.00 (2H, m, indane C(2)H₂)

HPLC (Luna 2, gradient 1): rt=3.21 minutes.

LC/MS (Luna 2, gradient 4): rt=1.78 minutes; 422 (MH)⁺.

Examples 80–95 were prepared in the same manner as example 1, using theindicated amine.

Example 80 3-(Aminomethyl)benzoyl-D-phenylglycine8-acetoxyquinolin-2-amide trifluoroacetate salt

From 8-acetoxyquinolin-2-amine.

¹H NMR (D₂O): 8.12–7.16 (14H, m, Ar); 5.50 (1H, s, α-CH); 4.00 (2H, brs, CH ₂NH₂); 2.13 (3H, s, CH ₃).

HPLC (Symmetry, Gradient 2): rt=6.02 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.99 minutes, 469 (MH)⁺.

Example 81 3-(Aminomethyl)benzoyl-D-phenylglycine3-ethoxycarbonyl-4,5-dimethylthiophen-2-amide trifluoroacetate salt

From 3-ethoxycarbonyl-4,5-dimethylthiophen-2-amine.

¹H NMR (d₆ DMSO): 11.32 (1H, NHAr); 9.37 (1H, d, J=7 Hz, NHCOAr); 8.10(2H, br s, NH ₂); 7.98 (2H, s, Ar); 7.58–7.27 (7H, m, Ar); 5.95 (1H, d,J=7 Hz, α-CH); 4.20 (2H, m, CH ₂N & CH ₂CH₃); 2.19 & 2.11 (2×3H, 2×s, 2×ArCH ₃); 1.17 (3H, t, J=7 Hz, CH₂CH ₃).

HPLC (Luna 2, Gradient 1): rt=4.72 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.23 minutes, 466 (MH)⁺.

Example 82 3-(Aminomethyl)benzoyl-D-phenylglycine5-acetyl-4-methylthiazol-2-amide trifluoroacetate salt

From 5-acetyl-4-methylthiazol-2-amine.

¹H NMR (d₃ acetonitrile): 8.92 (1H, d, J=6 Hz, NHCH); 7.95 (2H, br s, NH₂); 7.78–7.65 (2H, m, Ar); 7.40–7.14 (7H, m, Ar); 5.61 (1H, d, J=6 Hz,α-CH); 3.87 (2H, br d, J=5 Hz, CH ₂NH₂); 2.32 (3H, s, CH ₃); additionalmethyl group concealed by solvent peak between 2.20 and 2.30 ppm.

HPLC (Luna 2, Gradient 1): rt=3.55 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.78 minutes, 423 (MH)⁺.

Example 83 3-(Aminomethyl)benzoyl-D-phenylglycine5-phenylthiazol-2-amide trifluoroacetate salt

From 5-phenylthiazol-2-amine.

¹H NMR (d₃ acetonitrile): 12.81 (1H, s, H-bonded NHAr); 9.07 (1H, d, J=6Hz, NHCO); 8.12 (2H, br s, CH ₂NH₂); 8.07–7.84 (3H, m, Ar); 7.62–7.28(12H, m, Ar); 5.88 (1H, d, J=6 Hz, α-CH); 4.10 (2H, m, CH ₂NH₂).

HPLC (Luna 2, Gradient 1): rt=4.36 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.23 minutes, 443 (MH)⁺.

Example 84 3-(Aminomethyl)benzoyl-D-phenylglycine4,5-dimethyl-thiazol-2-amide trifluoroacetate salt

From 4,5-dimethylthiazol-2-amine.

¹H NMR (d₄ methanol): 9.01 (0.5H due to partial exchange, d, J=6 Hz,NHCH); 7.99–7.93 (2H, m, Ar); 7.61–7.43 (7H, m, Ar); 5.85 (1H, ssuperimposed upon d, J=6 Hz, α-CH); 4.18 (2H, s, CH ₂NH₂); 2.29 & 2.18(2×3H, 2×s, 2× CH ₃).

HPLC (Luna 2, Gradient 1): rt=3.67 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.96 minutes, 395 (MH)⁺.

Example 85 3-(Aminomethyl)benzoyl-D-phenylglycine4-methyl-5-ethoxycarbonylthiazol-2-amide trifluoroacetate salt

From 4-methyl-5-ethoxycarbonylthiazol-2-amine.

¹H NMR (d₃ acetonitrile): 8.20 (1H, d, J=6 Hz, NHCH); 8.02 (1H, s, Ar);7.76 (1H, d, J=7 Hz, Ar); 7.52–7.30 (7H, m, Ar); 5.78 (1H, d, J=6 Hz,α-CH); 4.16 (2H, q, J=6 Hz, CH ₂CH₃); 4.11 (2H, s, CH ₂NH₂); 2.45 (3H,s, ArCH ₃); 1.21 (3H, t, J=6 Hz, CH ₂CH₃).

HPLC (Luna 2, Gradient 1): rt=3.73 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.13 minutes, 453 (MH)⁺.

Example 86 3-(Aminomethyl)benzoyl-D-phenylglycine3-cyano-4-methyl-5-ethoxycarbonylthiophen-2-amide trifluoroacetate salt

From 3-cyano-4-methyl-5-ethoxycarbonylthiophen-2-amine.

¹H NMR (d₃ acetonitrile): 8.57 (1H, d, J=6 Hz, NHCH); 8.40 (1H, Ar);8.12 (1H, d, J=7 Hz, Ar); 7.81–7.59 (7H, m, Ar); 6.15 (1H, d, J=6 Hz,α-CH); 4.45 (2H, q, J=7 Hz); 4.40 (2H, s, CH ₂NH₂); 2.68 (3H, s, ArCH₃); 1.48 (3H, t, J=7 Hz, CH₂CH ₃).

HPLC (Luna 2, Gradient 1): rt=4.305 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.15 minutes, 477 (MH)⁺.

Example 87 3-(Aminomethyl)benzoyl-D-phenylglycine4-(methoxycarbonylmethyl)-5-methylthiazol-2-amide trifluoroacetate salt

From 4-methoxycarbonyl-5-methylthiazol-2-amine.

¹H NMR (d₃ acetonitrile): 8.02–7.97 (2H, m, Ar & NHCH); 7.87 (1H, d, J=8Hz, Ar); 7.59–7.33 (7H, m, Ar); 7.21 (2H, br s, NH ₂); 5.81 (1 h, d, J=6Hz, α-CH); 4.18 (2H, s, CH ₂NH-2); 3.58 (3H, s, CO₂CH ₃); 3.55 (2H, s,CH ₂CO); 2.31 (3H, s, ArCH ₃).

HPLC (Luna 2, Gradient 1): rt=3.54 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 453 (MH)⁺.

Example 88 3-(Aminomethyl)benzoyl-D-phenylglycine5-t-butyl-2-methoxycarbonylthiophen-3-amide trifluoroacetate salt

From 5-t-butyl-2-methoxycarbonylthiophen-3-amine.

¹H NMR (d₃ acetonitrile): 10.42 (1H, s, NHAr); 8.21 (1H, d, J=6 Hz,NHCH); 8.04 (1H, s, Ar); 7.80–7.65 (5H, m, 3× Ar & NH ₂); 7.52–7.30 (7H,Ar); 5.68 (1H, d, J=6 Hz, α-CH); 4.12 (2H, s, CH ₂NH₂); 3.72 (3H, s,CO₂CH ₃); 1.29 (9H, s, C(CH ₃)₃).

HPLC (Luna 2, Gradient 1): rt=4.93 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.48 minutes, 480 (MH)⁺.

Example 89 3-(Aminomethyl)benzoyl-D-phenylglycine5,6-dihydro-3-methoxycarbonyl-4H-cyclopenta(b)thiophen-2-amidetrifluoroacetate salt

From 5,6-dihydro-3-methoxycarbonyl-4H-cyclopenta(b)thiophen-2-amine.

¹H NMR (d₃ acetonitrile): 8.30 (1H, d, J=6 Hz, NHCH); 8.04 (1H, Ar);7.85 (1H, d, J=8 Hz, Ar); 7.62–7.30 (7H, m, Ar); 5.80 (1H, d, J=6 Hz,α-CH); 4.16 (2H, s, CH ₂NH₂); 3.72 (3H, s, CH ₃); 2.87 & 2.84 (2×2H,2×t, 2×J=6 Hz, CH ₂CH ₂CH₂); 2.30 (2H, pentet, J=6 Hz, CH₂CH ₂CH₂).

HPLC (Symmetry, Gradient 2): rt=6.56 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.26 minutes, 464 (MH)⁺.

Example 90 3-(Aminomethyl)benzoyl-D-phenylglycine3-ethoxycarbonyl-tetrahydrobenzo(b)thiophene-2-amide trifluoroacetatesalt

From 3-ethoxycarbonyl-tetrahydrobenzo(b)thiophene-2-amine.

¹H NMR (d₃ acetonitrile): 8.25 (0.6H due to partial exchange, d, J=6 Hz,NHCH); 8.06 (1H, s, Ar); 7.86 (1H, d, J=7 Hz, Ar); 7.52–7.23 (7H, m,Ar); 5.79 (1H, s superimposed upon d, J=6 Hz, α-CH); 4.18–4.04 (4H, m,CH ₂NH₂ & CH ₂CH₃); 2.65 & 2.50 (2×2H, 2×br s, CH ₂CH₂CH₂CH ₂);1.82–1.70 (4H, m, CH₂CH ₂CH ₂CH₂).

HPLC (Luna 2, Gradient 1): rt=5.15 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.42 minutes, 492 (MH)⁺.

Example 91 3-(Aminomethyl)benzoyl-D-phenylglycine2-acetyl-5-phenylthiophen-3-amide trifluoroacetate salt

From 2-acetyl-5-phenylthiophen-3-amine.

¹H NMR (d₃ acetonitrile): 8.34 (1H, s, thiophene CH); 8.30 (1H, d, J=6Hz, NHCH); 8.12 (1H, s, Ar); 7.85 (1H, d, J=8 Hz, Ar); 7.70–7.33 (12H,m, Ar); 5.75 (1H, d, J=6 Hz, α-CH); 4.16 (2H, s, CH ₂NH₂); 2.35 (3H, s,CH ₃).

HPLC (Luna 2, Gradient 1): rt=4.75 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.64 minutes, 484 (MH)⁺.

Example 92 3-(Aminomethyl)benzoyl-D-phenylglycine3-benzyloxycarbonyl-tetrahydrobenzo(b)thiophene-2-amide trifluoroacetatesalt

From 3-benzyloxycarbonyl-tetrahydrobenzo(b)thiophene-2-amine.

¹H NMR (d₃ acetonitrile): 8.02–7.95 (2H, m, 1×Ar & NHCH); 7.92 (1H, d,J=7 Hz, Ar); 7.72–7.32 (12H, m, Ar); 5.81 (1H, d, J=6 Hz, α-CH); 5.22(2H, s, CH ₂Ar); 4.18 (2H, s, CH ₂NH₂); 2.70 & 2.59 (2×2H, 2× t, 2×J=5Hz CH ₂CH₂CH₂CH ₂); 1.82–1.68 (4H, m, CH₂CH ₂CH ₂CH₂).

HPLC (Luna 2, Gradient 1): rt=5.40 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.75 minutes, 554 (MH)⁺.

Example 93 3-(Aminomethyl)benzoyl-D-phenylglycine N-methylanilidetrifluoroacetate salt

From N-methyl aniline.

¹H NMR (d₄ MeOH): 7.70 (2H, s, Ar); 7.45–7.30 (3H, m, Ar); 7.21 (3H, m,Ar); 7.08 (3H, m, Ar); 6.90 (3H, m, Ar); 5.50 (1H, s, CHPh); 3.97 (2H,s, CH ₂NH₂); 3.14 (3H, s, Me)

HPLC (Luna 2, Gradient 1): rt=3.91 minutes.

HPLC (Symmetry, Gradient 2): rt=5.88 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.72 minutes, 374 (MH)⁺.

Example 94 3-(Aminomethyl)benzoyl-D-phenylglycine N-methylindan-5-amidetrifluoroacetate salt

From 5-N-methylaminoindane, prepared as described below.

5-N-methylaminoindane

Formic acid (98%, 0.90 mL, 1.10 g, 24 mmol) was added dropwise to astirred solution of acetic anhydride (1.85 mL, 2.0 g, 20 mmol) in THF(20 mL) at 0° C. After the addition the solution was heated at 60° C.for 2 hours. The mixture was cooled to room temperature and THF (2 mL)was added, followed by a solution of 5-aminoindane (1.0 g, 7.5 mmol)dissolved in THF (4 mL) and allowed to stir overnight.

The solvent was evaporated under reduced pressure to give acream-coloured solid. This was dissolved in THF (10 mL), cooled to 0°C., and borane:dimethyl sulphide complex in THF (2.0M, 8.45 mL, 17 mmol)was added dropwise. The resulting mixture was heated at reflux for 3hours before being cooled to 0° C. Methanol (5 mL) was added and themixture stirred for 1 hour. Ethereal HCl (1.0 M, 10 mL) was added andthe mixture was warmed to 60° C. briefly, before being cooled back toroom temperature. Methanol 20 mL) was added and the solvents evaporatedunder reduced pressure. The solid residue was made basic (pH>12) withaqueous sodium hydroxide (2 N), then extracted with ether (2×20 mL). Thecombined dried extracts were absorbed onto silica and purified by flashchromatography using dichloromethane as eluent to give the amine as astraw-coloured oil upon evaporation (900 mg, 81%).

3-(Aminomethyl)benzoyl-D-phenylglycine N-methylindan-5-amidetrifluoroacetate salt

¹H NMR (d₄ MeOH): 7.91 (2H, m, Ar); 7.65 (1H, m, Ar); 7.55 (1H, m, Ar);7.35–7.20 (4H, m, Ar); 7.1 (2H, m, Ar); 6.87 (2H, br s, Ar); 5.73 (2H,d, J=7 Hz, CHPh); 4.18 (2H, s, CH ₂NH₂); 3.30 (3H, s, Me); 2.95 (2H, t,J=7.5 Hz, indane C(1)H₂ or C(3)H₂); 2.85 (2H, t, J=7.5 Hz, indane C(1)H₂or C(3)H₂); 2.13 (2H, quintet, J=7.5 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.11 minutes.

HPLC (Symmetry, Gradient 2): rt=6.30 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.10 minutes, 414 (MH)⁺.

Example 95 3-(Aminomethyl)benzoyl-D-phenylglycine1-methoxycarbonylmethyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From 6-amino-1-methoxycarbonylmethylindoline, prepared as describedbelow.

6-amino-1-methoxycarbonylmethylindoline

A suspension of 6-nitroindoline (1.0 g, 6.1 mmol) and sodium hydrogencarbonate (0.6 g, 7.1 mmol) in DMF (60 ml) was stirred at roomtemperature. Methyl bromoacetate (0.68 mL, 1.09 g, 7.1 mmol) was addedslowly and the mixture was heated at 90° C. for 1 hour. The mixture wascooled, the solvents evaporated under reduced pressure, and the residuepartitioned between ethyl acetate (40 mL) and water (20 mL). The organiclayer was dried over MgSO₄ and then evaporated to give an orange solid.The solid was dissolved in methanol (100 ml), 5% Pd/C (50 mg, cat.) wasadded and the suspension was stirred under an atmosphere of hydrogen for2 hours, during which time the yellow colour disappeared. The catalystwas removed by filtration through celite and the solvent was evaporatedto give the amine as a brown oil (0.95 g, 75%).

3-(Aminomethyl)benzoyl-D-phenylglycine1-methoxycarbonylmethyl-2,3-dihydroindol-6-amide trifluoroacetate salt

¹H NMR (d₄ MeOH): 7.75 (2H, br s, Ar); 7.38 (4H, m, Ar); 7.20 (3H, m,Ar); 6.75 (2H, d, J=8 Hz, Ar); 6.55 (2H, m, Ar); 5.61 (1H, s, CHPh);3.96 (3H, s, CH₃); 3.75 (2H, s, CH ₂NH₂); 3.5 (2H, s, CH₂CO₂Me); 3.3(2H, t, J=8.0 Hz, indoline C(2)H₂); 2.73 (2H, t, J=8.0 Hz, indolineC(3)H₂).

HPLC (Symmetry, Gradient 2): rt=6.06 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 473 (MH)⁺.

Example 96 3-(Aminomethyl)benzoyl-D/L-phenylglycine3-morpholinoyl-tetrahydrobenzo(b)thiophene-2-amide trifluoroacetate salt3-(BOC-Aminomethyl)benzoyl-D-phenylglycine3-(hydroxycarbonyl)tetrahydrobenzo(b)thiophen-2-amide

A solution of 3-(BOC-aminomethyl)benzoyl-D/L-phenylglycine3-benzyloxycarbonyl-tetrahydrobenzo(b)thiophen-2-amide (a protected formof example 92 and an intermediate in its synthesis) (1.00 g, 1.6 mmol)in methanol (20 mL) was stirred over 10% palladium on carbon under ahydrogen atmosphere for two hours. The mixture was filtered and themethanol evaporated under reduced pressure to afford the acid (0.86 g,quant.) which was used without further purification.

¹H NMR (d₆ DMSO): 11.91 (1H, br s CO₂ H); 9.46 (1H, d, J=6 Hz, NHCH);7.90 (1H, d, J=6 Hz, NHBoc); 7.86 (1H, s, Ar); 7.55–7.32 (7H, m, Ar);5.92 (1H, d, J=6 Hz, α-CH); 4.20 (2H, d, J=6 Hz, CH ₂NH₂); 2.71 & 2.59(2×2H, 2×br s, CH ₂CH₂CH₂CH ₂); 1.72–1.60 (4H, m, CH₂CH ₂CH ₂CH₂); 1.34(9H, s, C(CH ₃)₃)-3-(Aminomethyl)benzoyl-D-phenylglycine3-morpholinoyl-tetrahydrobenzo(b)thiophene-2-amide trifluoroacetatesalt.

A solution of the carboxylic acid (55 mg, 0.10 mmol) in DMF (2 mL) wasstirred at room temperature and diisopropylethylamine (52 μL, 39 mg,0.30 mmol), morpholine (87 μL, 87 mg, 1.00 mmol) andO-(7-azabenzotriazol-1-yl)-N′,N′,N′,N′-tetramethyluroniumhexafluorophosphate (114 mg, 0.30 mmol). The reaction was allowed tostir at room temperature until HPLC indicated complete consumption ofstarting material (5 days). Ethyl acetate (20 mL) was then added, andthe solution extracted with 1N HCl (20 mL); sodium bicarbonate (sat.,aq., 20 mL) and water (20 mL); dried over MgSO₄, concentrated underreduced pressure, and purified by flash column chromatography.

A solution of the amide in dichloromethane (2 mL) was treated withtrifluoroacetic acid (2 mL) for an hour. The excess TFA anddichloromethane were evaporated and the residue purified by triturationwith diethyl ether to afford 3-(Aminomethyl)benzoyl-D/L-phenylglycine3-morpholinoyl-tetrahydrobenzo(b)thiophene-2-amide as itstrifluoroacetate salt.

¹H NMR (d₃ acetonitrile): 9.02 ppm (1H, s, NHAr); 7.85–7.70 (3H, m, NHCH& 2×Ar); 7.50–7.25 (7H, m, Ar); 5.64 (1H, d, J=6 Hz, α-CH); 4.03 (2H, brs, CH ₂NH₂); 3.40–2.89 (8H, m, 2×CH ₂O & CH ₂CH₂CH₂CH ₂); 2.52–2.45 &2.30–2.15 (2×2H, 2×m, 2× morpholine CH ₂N); 1.75–1.60 (4H, m, CH₂CH ₂CH₂CH₂).

HPLC (Luna 2, Gradient 1): rt=3.68 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.91 minutes, 533 (MH)⁺.

Examples 97–101 were prepared from3-(N-BOC-aminomethyl)benzoyl-D/L-phenylglycine 3-(hydroxycarbonyl)tetrahydrobenzo(b)thiophen-2-amide in the same manner as example 96,using the indicated amine.

Example 97 3-(Aminomethyl)benzoyl-D-phenylglycine3-benzylamido-tetrahydrobenzo(b)thiophen-2-amide trifluoroacetate salt

Prepared from benzylamine.

¹H NMR (d₃ acetonitrile): 8.02–7.91 (3H, m, 2×Ar & NHCH); 7.60–7.25(12H, m, Ar); 6.73 (1H, t, J=5 Hz, NHBn); 5.79 (1H, d, J=6 Hz, α-CH);4.41 (2H, d, J=5 Hz, CH ₂Ar); 4.16 (2H, s, CH ₂NH₂); 2.71 & 2.62 (2×2H,2×br s, CH ₂CH₂CH₂CH ₂); 1.85–1.76 (4H, m, CH₂CH ₂CH ₂CH₂).

HPLC (Luna 2, Gradient 1): rt=4.47 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.40 minutes, 553 (MH)⁺.

Example 98 3-(Aminomethyl)benzoyl-D-phenylglycine3-pyridylmethylamido-tetrahydrobenzo(b)thiophen-2-amidebis-trifluoroacetate salt

Prepared from 3-pyridylmethylamine.

¹H NMR (d₃ acetonitrile): 8.37 (1H, s, Ar); 8.34 (1H, d, J=5 Hz, NHCH);8.25 (1H, d, J=6 Hz, Ar); 7.78–7.14 (11H, m, Ar); 6.81 (1H, t, J=5 Hz,NHBn); 5.58 (1H, d, J=5 Hz, α-CH); 4.42 (2×1H, 2×dd, 2×J=8 Hz, 5 Hz,NHCH ₂Ar); 4.04 (2H, s, CH ₂NH₂); 2.58 & 2.46 (2×2H, 2×br s, CH₂CH₂CH₂CH ₂); 1.62–1.53 (4H, m, CH₂CH ₂CH ₂CH₂).

HPLC (Luna 2, Gradient 1): rt=3.32 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.59 minutes, 554 (MH)⁺.

Example 99 3-(Aminomethyl)benzoyl-D-phenylglycine3-piperidinoyl-tetrahydrobenzo(b)thiophen-2-amide trifluoroacetate salt

Prepared from piperidine.

¹H NMR (d₃ acetonitrile): 9.20 (1H, s, NHAr); 8.15–7.26 (9H, m, Ar);5.82 (1H, br s, α-CH); 4.06 (2H, br s, CH ₂NH₂); 3.20–1.15 (18H, m,piperidyl and cyclohexyl protons)

HPLC (Luna 2, Gradient 1): rt=3.94 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.02 minutes, 531 (MH)⁺.

Example 100 3-(Aminomethyl)benzoyl-D-phenylglycine3-cyclopropylmethylamido-tetrahydrobenzo(b)thiophen-2-amidetrifluoroacetate salt

Prepared from cyclopropylmethylamine.

¹H NMR (d₃ acetonitrile): 7.76–7.58 (3H, m, 2×Ar & NHCH); 7.40–7.12 (7H,m, Ar); 6.18 (1H, t, J=5 Hz, NHBn); 5.50 (1H, d, J=5 Hz, α-CH); 4.00(2H, br s, CH ₂NH₂); 2.92 (2H, t, J=5 Hz, CH ₂CPr); 2.48 & 2.40 (2×2H,2×br s, CH ₂CH₂CH₂CH ₂); 1.65–1.55 (4H, m, CH₂CH ₂CH ₂CH₂); 0.81–0.65,0.28–0.17 & 0.05 to −0.05 (1H, 2H & 2H, 3×m, cPr protons).

HPLC (Luna 2, Gradient 1): rt=4.19 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.18 minutes, 517 (MH)⁺.

Example 101 3-(Aminomethyl)benzoyl-D-phenylglycine3-(1,3-dimethylbutyl)amido-tetrahydrobenzo(b)thiophen-2-amidetrifluoroacetate salt

Prepared from racemic 1,3-dimethylbutylamine.

¹H NMR (d₃ acetonitrile): 7.88–7.75 (3H, m, 2×Ar & NHCH); 7.48–7.25 (7H,m, Ar); 5.97 (1H, d, J=5 Hz, α-CH); 5.68 & 5.65 (2×0.5H, 2×d, 2×J=4 Hz,NHHex); 4.12–4.02 (2H, m, CH ₂NH₂); 4.01–3.90 (1H, m, CH₃CHNH); 2.59 &2.47 (4H, m, CH ₂CH₂CH₂CH ₂); 1.73–1.62 (4H, m, CH₂CH ₂CH ₂CH₂);1.53–0.70 (12H, m, remaining hexyl protons).

HPLC (Luna 2, Gradient 1): rt=4.63 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.53 minutes, 547 (MH)⁺.

Example 102 3-(Aminomethyl)benzoyl-D-phenylglycine3-carboxy-tetrahydrobenzo(b)thiophen-2-amide trifluoroacetate salt

A solution of 3-(BOC-aminomethyl)benzoyl-D/L-phenylglycine3-(hydroxycarbonyl)tetrahydrobenzo(b)thiophen-2-amide (50 mg, 0.9 mmol),the compound from which examples 96–100 were made, in dichloromethane (2mL) was treated with trifluoroacetic acid (2 mL) for an hour at roomtemperature. The solvents were evaporated and the residue trituratedwith diethyl ether to afford the title compound as an off-white solid.

¹H NMR (d₃ acetonitrile): 8.25–8.17 (2H, m, Ar); 8.01 (1H, d, J=6 Hz,NHCH); 7.75–7.52 (7H, m, Ar); 6.00 (1H, d, J=6 Hz, α-CH); 4.35 (2H, brs, CH₂NH₂); 2.85 & 2.71 (2×2H, 2×br s, CH ₂CH₂CH₂CH ₂); 1.92–1.80 (4H,m, CH₂CH₂CH₂CH₂.

HPLC (Luna 2, Gradient 1): rt=4.31 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.07 minutes, 464 (MH)⁺.

Examples 103–118 were prepared from the intermediate3-(N-BOC-aminomethyl)benzoyl-D/L-phenylglycine 2,3-dihydroindol-6-amide,described for example 35, using the indicated carboxylic acid orderivative, using standard chemical methods and protecting otherfunctionality where required.

Example 103 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(3-acetylamino)propionyl-2,3-dihydroindol-6-amide hydrochloride salt

From N-acetyl-β-alanine.

¹H NMR (CD₃CN): 8.78 ppm (1H, br s, NH); 8.40 (1H, br s, NH); 7.82 (2H,br s, Ar); 7.72 (1H, d, J=10 Hz, Ar); 7.62–7.53 (2H, m, Ar); 7.51 (1H,d, J=10 Hz, Ar); 7.45–7.27 (4H, m, Ar); 7.20 (1H, d, J=9 Hz, indolineC(4)H or C(5)H); 7.10 (1H, d, J=9 Hz, indoline C(4)H or C(5)H ); 6.68(1H, br s, NH); 5.71 (1H, d, J=8 Hz, CHPh); 4.00 (2H, t, J=9 Hz,indoline C(2)H₂); 3.83 (2H, s, CH ₂NH₂); 3.42 (2H, q, J=6 Hz, AcNHCH₂CH₂); 3.06 (2H, t, J=11 Hz, indoline C(3)H₂); 2.54 (2H, t, J=6 Hz,AcNHCH ₂CH₂); 1.86 (3H, s, CH₃CO).

HPLC (Symmetry C8, Gradient 2): rt=5.57 min.

LC/MS (Luna 2, Gradient 4): rt=1.62 min, 514 (MH)⁺.

Example 104 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-amidoacetyl-2,3-dihydroindol-6-amide hydrochloride salt

From malonic acid monoamide.

¹H NMR (CD₃CN): 8.66 ppm (1H, br s, NH); 8.35 (1H, br s, NH); 7.94 (1H,s, Ar); 7.85 (1H, s Ar); 7.78–7.65 (3H, m, Ar); 7.60–7.52 (2H, m, Ar);7.50 (1H, d, J=8 Hz, Ar); 7.46–7.31 (4H, m, Ar); 7.25 (1H, d, J=10 Hz,indoline C(4)H or C(5)H); 7.12 (1H, d, J=10 Hz, indoline C(4)H orC(5)H); 6.77 (1H, br s, C(O)NH _(a)H_(b)); 5.85 (1H, br s, C(O)NH_(a) H_(b)); 5.67 (1H, d, J=9 Hz, CHPh); 4.08 (2H, t, J=10 Hz, indolineC(2)H₂); 3.86 (2H, s, CH ₂NH₂); 3.38 (2H, s, C(O)CH₂C(O)); 3.11 (2H, t,J=10 Hz, indoline C(3)H₂).

HPLC (Symmetry C8, Gradient 2): rt=5.12 min.

LC/MS (Luna 2, Gradient 4): rt=1.67 min, 486 (MH)⁺.

Example 105 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(γ-L-aspartoyl)-2,3-dihydroindol-6-amide bis(hydrochloride) salt

From N-BOC-aspartic acid 1-t-butyl ester.

¹H NMR (D₂O): 7.89 ppm (1H, d, J=8 Hz, Ar); 7.62 (1H, s, Ar); 7.60 (1H,d, J=8 Hz, Ar); 7.52–7.11 (7H, m, Ar); 6.95–6.72 (2H, m, indoline C(4)Hand C(5)H); 5.53 (1H, s, CHPh); 4.44 (1H, m, CH(NH₂)CO₂H); 4.01 (2H, s,CH ₂NH₂); 3.85–3.50 (2H, m, indoline C(2)H₂); 3.00–2.55 (4H, m, indolineC(3)H₂ and C(O)CH ₂CH(NH₂)CO₂H).

HPLC (Symmetry C8, Gradient 2): rt=5.26 min.

LC/MS (Luna 2, Gradient 4): rt=1.29 min, 516 (MH)⁺.

Example 106 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(β-glutamoyl)-2,3-dihydroindol-6-amide bis(hydrochloride) salt

From N-BOC-β-glutamic acid 5-benzyl ester.

¹H NMR (D₂O): 7.83 ppm (1H, d, J=10 Hz, Ar); 7.63 (2H, br s,3-(aminomethyl)-phenyl C(2)H and C(6)H); 7.55–7.17 (6H, m, Ar); 6.88(1H, br s, Ar); 6.82 (1H, d, J=9 Hz, indoline C(4)H or C(5)H); 6.64 (1H,d, J=8 Hz, indoline C(4)H or C(5)H); 5.55 (1H, s, CHPh); 4.00 (2H, s, CH₂NH₂); 3.80 (1H, quintet, J=6 Hz, CHNH₂); 3.30–3.06 (2H, br m, indolineC(2)H₂); 2.71 (2H, d, J=6 Hz, β-glutamoyl C(2)H₂ or C(4)H₂); 2.60–2.25(4H, br m, indoline C(3)H₂ and β-glutamoyl C(2)H₂ or C(4)H₂).

HPLC (Symmetry C8, Gradient 2): rt=5.39 min.

LC/MS (Luna 2, Gradient 4): rt=1.18 min, 530 (MH)⁺.

Example 107 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(L-homoprolinoyl)-2,3-dihydroindol-6-amide bis(hydrochloride) salt

From N-BOC-homoproline.

¹H NMR (D₂O): 7.76 ppm (1H, s, Ar); 7.56 (2H, br s, Ar); 7.40–7.14 (7H,m, Ar); 6.83–6.67 (2H, m, indoline C(4)H and C(5)H); 5.43 (1H, s, CHPh);3.92 (2H, s, CH ₂NH₂); 3.61–3.53 (1H, m, pyrrolidine C(2)H); 3.42–3.29(2H, m, indoline C(2)H₂); 3.05 (2H, t, J=6 Hz, pyrrolidine C(5)H₂);2.55–2.41 (4H, m, C(O)CH₂Pyrrolidine and indoline C(3)H₂); 1.98–1.87(1H, m, pyrrolidine C(3)H or C(4)H); 1.80–1.66 (2H, m, pyrrolidine C(3)Hor C(4)H); 1.48–1.35 (1H, m, pyrrolidine C(3)H or C(4)H).

HPLC (Symmetry C8, Gradient 2): rt=5.36 min.

LC/MS (Luna 2, Gradient 4): rt=1.32 min, 512 (MH)⁺.

Example 108 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(D-pipecoloyl)-2,3-dihydroindol-6-amide bis(hydrochloride) salt

From N-BOC-D-pipecolic acid.

¹H NMR (D₂O): 8.05 ppm (1H, s, Ar); 7.80 (2H, br s, Ar); 7.72–7.30 (7H,m, Ar); 7.03 (1H, d, J=8 Hz, indoline C(4)H or C(5)H); 6.88 (1H, d, J=8Hz, indoline C(4)H or C(5)H); 5.72 (1H, s, CHPh); 4.18 (2H, s, CH ₂NH₂);3.84–3.53 (2H, m, indoline C(2)H₂); 3.43–2.60 (7H, m, indoline C(3)H₂,piperidine C(2)H₂, C(3)H and C(6)H₂); 2.00–1.48 (4H, m, piperidineC(4)H₂ and C(5)H₂).

HPLC (Symmetry C8, Gradient 2): rt=5.38 min.

LC/MS (Luna 2, Gradient 4): rt=1.24 min, 512 (MH)⁺.

Example 109 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(trans-2-aminocyclohexanoyl)-2,3-dihydroindol-6-amidebis(hydrochloride) salt

From N-BOC-trans-2-aminocyclohexane carboxylic acid.

¹H NMR (D₂O): 7.78 (1H, d, J=9 Hz, Ar); 7.48 (2H, br s, Ar); 7.36–6.95(7H, m, Ar); 6.67 (1H, d, J=8 Hz, indoline C(4)H or C(5)H); 6.62 (1H, d,J=8 Hz, indoline C(4)H or C(5)H); 5.32 (1H, s, CHPh); 3.88 (2H, s, CH₂NH₂); 3.77–3.41 (2H, m, indoline C(2)H₂); 3.14 (1H, td, J=12, 5 Hz,cHex C(2)H); 2.64–2.42 (2H, m, indoline C(3)H₂); 2.32 (1H, br s, cHexC(1)H); 1.74 (1H, br d, J=11 Hz, cHex H); 1.62 (1H, br s, cHex H); 1.43(2H, br d, J=12 Hz, cHex H's); 1.25–0.82 (4H, m, cHex H's).

HPLC (Symmetry C8, Gradient 2): rt=5.25 min.

LC/MS (Luna 2, Gradient 4): rt=2.80 min, 526 (MH)⁺.

Example 110 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(cis-2-aminocyclohexanoyl)-2,3-dihydroindol-6-amide bis(hydrochloride)salt

From N-BOC-cis-2-aminocyclohexane carboxylic acid.

¹H NMR (D₂O): 7.80 (1H, d, J=11 Hz, Ar); 7.53 (1H, br s, Ar); 7.49 (1H,d, J=8 Hz, Ar); 7.38–7.27 (3H, m, Ar); 7.25–7.11 (4H, m, Ar); 6.71 (1H,d, J=10 Hz, indoline C(4)H or C(5)H); 6.60 (1H, d, J=10 Hz, indolineC(4)H or C(5)H); 5.44 (1H, s, CHPh); 3.86 and 3.80 (2H, AB quartet, J=14Hz, CH ₂NH₂); 3.46–3.28 (3H, m, indoline C(2)H₂ and cHex C(2)H);2.54–2.38 (3H, m, indoline C(3)H₂ and cHex C(1)H); 1.75–1.60 (1H, m,cHex H); 1.48–1.15 (6H, m, cHex H's); 1.10–0.97 (1H, m, cHex H).

HPLC (Symmetry C8, Gradient 2): rt=5.14 min.

LC/MS (Luna 2, Gradient 4): rt=2.72 min, 526 (MH)⁺.

Example 111 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(piperidin-4-ylacetyl)-2,3-dihydroindol-6-amide bis-trifluoroacetatesalt

From piperidin-4-ylacetic acid.

¹H NMR (D₂O): 8.01 (1H, s, NHAr); 7.70 (2H, s, Ar); 7.52–7.31 (10H, m,Ar); 7.12 & 6.96 (2×1H, 2×d, J=6 Hz, Ar); 5.51 (1H, s, α-CH); 4.12 (2H,s, CH₂NH₂); 3.94 (2H, t, J=7 Hz, indoline NCH ₂); 3.31 (1H, d, J=10 Hz,CH ₂C═O); 3.01 (2H, t, J=7 Hz, indoline ArCH ₂); 2.99–2.83, 2.40–2.32,2.08–1.94, 1.90–1.80 & 1.39–1.18 (2H, 2H, 1H, 2H & 2H, 5×m, piperidylring protons).

HPLC (Luna 2, Gradient 1): rt=5.06 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.45 minutes, 526 (MH)⁺.

Example 112 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-[(4-aminomethyl)phenylacetyl]-2,3-dihydroindol-6-amidebis-trifluoroacetate salt

From 4-(BOC-aminomethyl)phenylacetic acid.

¹H NMR (d₆ DMSO): 10.30 (1H, s, NHAr); 8.85 (1H, d, J=8 Hz, NHCOAr);8.28 & 8.01 (2×1H, 2×s, Ar); 7.96 (1H, d, J=8 Hz, Ar); 7.68–7.14 (13H,m, Ar); 5.81 (1H, d, J=8 Hz, α-CH); 4.24–4.01 (6H, m, 3×CH₂NH ₂); 3.84(2H, s, ArCH ₂); 3.06 (2H, t, J=7 Hz, indoline ArCH ₂).

HPLC (Symmetry, Gradient 2): rt=5.51 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.62 minutes, 548 (MH)⁺.

Example 113 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-[(4-acetylaminomethyl)phenylacetyl]-2,3-dihydroindol-6-amidetrifluoroacetate salt

From 4-(acetylaminomethyl)phenylacetic acid.

¹H NMR (D₂O): 7.90 (1H, s, NH); 7.59–7.21 (10H, m, Ar); 6.98 & 6.85(2×2H, 2×d, 2×J=9 Hz, para-substituted ring protons); 6.78 & 6.75 (2×1H,2×d, 2×J 6 Hz, indoline CHCH); 5.48 (1H, s, α-CH); 4.11 & 4.01 (2×2H,2×s, 2×ArCH ₂N); 3.67 (2H, t, J=6 Hz, indoline CH ₂N); 3.37 (2H, s, CH₂CO); 2.62 (2H, t, J=6 Hz, indoline ArCH ₂); 1.81 (3H, s, CH ₃).

HPLC (Symmetry, Gradient 2): rt=5.87 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.94 minutes, 590 (MH)⁺.

Example 114 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-[(4-isopropyl)phenylacetyl]-2,3-dihydroindol-6-amide trifluoroacetatesalt

From 4-(isopropyl)phenylacetic acid.

¹H NMR (d₃ acetonitrile): 9.06 (1H, s, NHAr); 8.34 (1H, s, Ar); 8.06(1H, d, J=7 Hz, NHCOAr); 8.01–7.04 (15H, Ar); 5.71 (1H, d, J=6 Hz,α-CH); 4.17–4.06 (4H, m, 2×CH ₂N); 3.70 (2H, s, CH₂CO); 3.08 (2H, t, J=7Hz, indoline ArCH₂); 2.90 (1H, septet, J=7 Hz, CHMe₂); 1.19 (6H, d, J=7Hz, 2×CH ₃).

HPLC (Symmetry, Gradient 2): rt=6.89 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.64 minutes, 561 (MH)⁺.

Example 115 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-[(3,4-dihydroxyphenyl)acetyl]-2,3-dihydroindol-6-amidetrifluoroacetate salt

From 3,4-dihydroxyphenylacetic acid.

¹H NMR (d₆ DMSO): 10.50 (1H, s, H-bonded OH); 9.00–8.90 (2H, m, Ar);8.90 (1H, br s, OH); 8.45 (1H, s, NH); 8.25 (2H, br s, NH ₂); 8.16 (1H,s, NH); 8.07 (1H, d, J=8 Hz, Ar); 7.76–7.46 (9H, m, Ar); 6.79–6.71 (2H,m, Ar); 6.59 (1H, d, J=8 Hz, Ar); 5.93 (1H, d, J=7 Hz, α-CH); 4.27–4.12(4H, m, 2×CH ₂N); 3.70 (1H, s, CH ₂CO); 3.15 (2H, t, J=7 Hz, indolineArCH ₂).

HPLC (Symmetry, Gradient 2): rt=5.90 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.94 minutes, 551 (MH)⁺.

Example 116 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(4-aminocyclohexyl)acetyl-2,3-dihydroindol-6-amidebis-trifluoroacetate salt

From 4-(BOC-aminocyclohexyl)acetic acid.

¹H NMR (d₃ acetonitrile): 9.04 (1H, s, NHAr); 8.15 (1H, Ar); 7.90–6.85(11H, m, Ar); 5.54 (1H, d, J=6 Hz, α-CH);); 3.95–3.74 (5H, m, 2×CH ₂NH₂& CHNH₂); 2.87 (2H, t, J=7 Hz, indoline ArCH ₂); 2.65–1.84 (11H, m,cyclohexyl protons & adjacent CH ₂).

HPLC (Luna 2, Gradient 1): rt=3.23 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.45 minutes, 540 (MH)⁺.

Example 117 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(isobutyrylaminoacetyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

From N-isobutyryl glycine.

¹H NMR (d₄ MeOH): 8.23 (1H, s, Ar); 8.85 (2H, m, Ar); 7.50 (4H, m, Ar);7.30 (4H, m, Ar); 7.10 (1H, d, J=8 Hz, Ar); 5.72 (1H, s, CHPh);4.10–4.01 (6H, m, CH ₂NH₂, CH₂indoline, COCH₂); 3.10 (2H, t, J=8 Hz,CH₂indoline); 2.50 (1H, septet, J=7 Hz, CH(Me)₂); 1.10 (6H, d, J=7 Hz,CH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=3.39 minutes.

HPLC (Symmetry, Gradient 2): rt=5.75 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.72 minutes, 528 (MH)⁺

Example 118 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-[hydroxyacetyl(aminoacetyl)]-2,3-dihydroindol-6-amide trifluoroacetatesalt

From N-(2-benzyloxyacetyl)glycine.

¹H NMR (d₄ MeOH): 8.15 (1H, s, Ar); 7.78 (2H, m, Ar); 7.42 (4H, m, Ar);7.32 (4H, m, Ar); 7.0 (1H, d, J=8 Hz, Ar); 5.65 (1H, s, CHPh); 4.05–3.95(6H, m, CH ₂NH₂, indoline C(2)H₂, COCH₂NH); 3.88 (2H, s, COCH ₂OH); 3.10(2H, t, J=8.5 Hz, indoline C(3)H₂).

HPLC (Luna 2, Gradient 4): rt=3.805 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.51 minutes, 516 (MH)⁺.

Example 119 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-methanesulfonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

A solution of 3-(N-BOC-aminomethyl)benzoyl-D/L-phenylglycine2,3-dihydroindolyl-6-amide (100 mg, 0.2 mmol) in dichloromethane (5 mL)was treated with triethylamine (42 μl, 0.3 mmol) and methanesulfonylchloride (23.2 μl, 0.3 mmol). The mixture was stirred overnight at roomtemperature, then diluted with further dichloromethane (10 mL). Thesolution was washed with water (2×15 mL) and brine (10 mL). The organicsolvent was dried over magnesium sulfate and the solvent removed underreduced pressure. The crude amide was dissolved in dichloromethane (5mL) and treated with trifluoroacetic acid (1 mL) for 2 hours, until HPLCindicated no starting material remained. The mixture was evaporatedunder reduced pressure, and the resulting gum triturated with diethylether (2×30 mL) to afford an off-white solid, which was isolated byfiltration. Purification via preparative HPLC yielded the title compoundas a white solid (38 mg, 32%).

¹H NMR (d₆ DMSO): 10.48 ppm (1H, s); 8.89 (1H, d, J=6 Hz, Ar); 8.03 (3H,br s, NH₃ ⁺); 7.95 (1H, d, J=8 Hz, Ar); 7.66 (1H, s); 7.63–7.30 (7H, m,Ar); 7.18 (1H, d, J=8 Hz, Ar); 5.85 (1H, d, J=7 Hz, CHPh); 4.09 (2H, s,CH ₂NH₂); 3.92 (2H, t, J=8 Hz, indolyl CH₂); 3.04 (2H, t, J=8 Hz,indolyl CH₂); 2.97 (3H, s, CH₃).

HPLC (Luna 2, Gradient 4): rt=2.37 minutes

LC/MS (Luna 2, Gradient 4): rt=1.70 minutes, 479 (MH)⁺.

Examples 120–125 were prepared in a similar manner to Example 119, usingthe indicated sulphonyl chloride.

Example 120 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-ethanesulfonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From ethanesulfonyl chloride.

¹H NMR (d₆ DMSO): 10.51 ppm (1H, s); 8.95 (1H, d, J=7 Hz, Ar); 8.20 (2H,s(br), NH₂); 8.08 (1H, s); 9.00 (1H, d, J=8 Hz); 7.68–7.32 (9H, m, Ar);7.21 (1H, d, J=9 Hz); 5.90 (1H, d, J=8 Hz, CHPh); 4.14 (2H, s, CH ₂NH₂);4.01 (2H, t, J=8 Hz, indolyl CH₂); 3.21 (2H, q, J=7.5 Hz, CH₂CH₃); 3.09(2H, t, J=9 Hz, indolyl CH₂); 1.24 (3H, t, J=7.5 Hz, CH₃).

HPLC (Luna 2, Gradient 4): rt=2.65 minutes

LC/MS (Luna 2, Gradient 4): rt=1.78 minutes, 493 (MH)⁺.

Example 121 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-benzenesulfonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From benzenesulfonyl chloride.

¹H NMR (d₆ DMSO): 10.40 ppm (1H, s); 8.87 (1H, d, J=7.5 Hz, Ar); 7.93(3H, m); 7.88 (1H, d, J=8 Hz, Ar); 7.83 (1H, d, J=1.5 Hz, Ar); 7.71 (2H,d, J=9 Hz); 7.51–7.26 (10H, m, Ar); 7.10 (1H, d, J=4 Hz, Ar); 6.96 (1H,d, J=8 Hz); 5.79 (1H, d, J=8 Hz, CHPh); 4.00 (2H, s, CH ₂NH₂); 3.78 (2H,t, J=8 Hz, indolyl CH₂); 2.73 (2H, t, J=8 Hz, indolyl CH₂).

HPLC (Luna 2, Gradient 4): rt=3.02 minutes

LC/MS (Luna 2, Gradient 4): rt=2.03 minutes, 541 (MH)⁺.

Example 122 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-benzylsulfonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From α-toluenesulfonyl chloride.

¹H NMR (d₆ DMSO): 10.43 ppm (1H, s); 8.92 (1H, d, J=7.5 Hz, Ar); 8.22(2H, br s, NH₂); 8.05 (1H, s); 7.97 (1H, d, J=7.5 Hz, Ar); 7.61–7.25(13H, m); 7.14 (1H, d, J=8 Hz, Ar); 5.88 (1H, d, J=8 Hz, CHPh); 4.53(2H, s, CH₂Ph); 4.10 (2H, s, CH ₂NH₂); 3.80 (2H, t, J=8.5 Hz, indolylCH₂); 2.94 (2H, t, J=8.5 Hz, indolyl CH₂).

HPLC (Luna 2, Gradient 4): rt=3.07 minutes

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 555 (MH)⁺.

Example 123 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-N,N-dimethylsulfamoyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From dimethylsulfamoyl chloride.

¹H NMR (d₆ DMSO): 10.42 ppm (1H, s); 8.90 (1H, d, J=8 Hz, Ar); 8.14 (2H,br s, NH₂); 8.02 (1H, s, Ar); 7.94 (1H, d, J=7.5 Hz); 7.63–7.51 (5H, m,Ar); 7.41–7.34 (3H, m, Ar); 7.23 (1H, d, J=8 Hz); 7.12 (1H, d, J=8 Hz);5.85 (1H, d, J=7.5 Hz, CHPh); 4.08 (2H, d, J=5 Hz, CH ₂NH₂); 3.90 (2H,t, J=8.5 Hz, indolyl CH₂); 3.03 (2H, t, J=8.5 Hz, indolyl CH₂); 2.79(6H, s, 2×CH₃).

HPLC (Luna 2, Gradient 4): rt=2.73 minutes

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 506 (MH)⁺.

Example 124 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(8-quinolyl-sulfonyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

From 8-quinolinesulfonyl chloride.

¹H NMR (d₆ DMSO): 10.30 ppm (1H, s); 9.01 (1H, d, J=2.5 Hz, Ar); 8.88(1H, d, J=8 Hz, Ar); 8.48 (2H, d, J=7 Hz, Ar); 8.27 (1H, d, J=7 Hz, Ar);8.03 (2H, br s, NH₂); 7.74 (1H, d, J=7 Hz, Ar); 7.73–7.33 (10H, m, Ar);7.06 (1H, d, J=7 Hz); 6.98 (1H, d, J=7 Hz); 4.70–4.56 (2H, m, indolylCH₂); 4.09 (2H, d, J=5.5 Hz, CH ₂NH₂); 2.99 (2H, t, J=8.5 Hz, indolylCH₂).

HPLC (Luna 2, Gradient 4): rt=2.55 minutes

LC/MS (Luna 2, Gradient 4): rt=1.95 minutes, 592 (MH)⁺.

Example 125 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-(2-naphthyl-sulfonyl)-2,3-dihydroindol-6-amide trifluoroacetate salt

From 2-naphthalenesulfonyl chloride.

¹H NMR (d₆ DMSO): 10.52 ppm (1H, s); 9.00 (1H, d, J=7.5 Hz, Ar); 8.61(1H, s, Ar); 8.17 (2H, br s, NH₂); 8.11–7.99 (6H, m, Ar); 7.80 (1H, d,J=7.5 Hz); 7.72–7.38 (9H, m, Ar); 7.11 (1H, d, J=7.5 Hz); 7.02 (1H, d,J=7.5 Hz); 5.90 (1 H, d, J=7.5 Hz, CHPh); 4.12 (2H, s, CH₂NH₂); 3.96(2H, t, J=8 Hz, indolyl CH₂); 2.85 (2H, t, J=8 Hz, indolyl CH₂).

HPLC (Luna 2, Gradient 4): rt=2.82 minutes

LC/MS (Luna 2, Gradient 4): rt=2.20 minutes, 591 (MH)⁺.

Examples 126–128 were prepared from3-(N-BOC-aminomethyl)benzoyl-D/L-phenylglycine2,3-dihydroindolyl-6-amide in a similar manner as example 119, exceptthat the indicated chloroformate was used in place of the sulphonylchloride.

Example 126 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-methoxycarbonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From methyl chloroformate.

¹H NMR (d₆ DMSO): 10.48 ppm (1H, s); 8.88 (1H, d, J=7.5 Hz); 8.17 (2H,br s, NH₂); 8.04 (1H, s); 7.96 (1H, d, J=7.5 Hz, Ar); 7.63–7.28 (8H, m,Ar); 7.12 (1H, d, 8 Hz); 5.87 (1H, d, J=7.5 Hz, CHPh); 4.10 (2H, d,J=4.5 Hz, CH ₂NH₂); 3.95 (2H, t, J=8.5 Hz, indolyl CH₂); 3.73 (3H, s,CH₃); 3.02 (2H, t, J=8.5 Hz, indolyl CH₂).

HPLC (Luna 2, Gradient 4): rt=2.35 minutes

LC/MS (Luna 2, Gradient 4): rt=1.80 minutes, 459 (MH)⁺.

Example 127 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-phenoxy-carbonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From phenyl chloroformate.

¹H NMR (d₆ DMSO): 10.42 ppm (1H, s); 8.87 (1H, d, J=7.5 Hz, Ar); 8.16(2H, br s, NH₂); 8.02 (1H, s, Ar); 7.94 (1H, d, J=7.5 Hz, Ar); 7.60–7.18(13H; m, Ar); 5.85 (1H, d, J=7.5 Hz, CHPh); 4.21 (2H, br s, indolylCH₂); 4.09 (2H, d, J=4 Hz, CH ₂NH₂); 3.12 (2H, t, J=7.5 Hz, indolylCH₂).

HPLC (Luna 2, Gradient 4): rt=2.71 minutes

LC/MS (Luna 2, Gradient 4): rt=2.15 minutes, 521 (MH)⁺.

Example 128 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-allyloxy-carbonyl-2,3-dihydroindol-6-amide trifluoroacetate salt

From allyl chloroformate.

¹H NMR (d₆ DMSO): 10.40 ppm (1H, s); 8.87 (1H, d, J=7.5 Hz, Ar); 8.16(2H, br s, NH₂); 8.04 (1H, s, Ar); 7.96 (1H, d, J=8 Hz, Ar); 7.61–7.28(8H, m, Ar); 7.13 (1H, d, J=8 Hz, Ar); 6.10–5.95 (1H, m, CH═CH₂); 5.35(1H, dd, J=17 Hz, 1.5 Hz, CH═CH ₂); 5.24 (1H, dd, J=10.5 Hz, 1.5 Hz,CH═CH ₂); 4.67 (2H, d, J=4.5 Hz, OCH₂); 4.10 (2H, d, J=4 Hz, CH ₂NH₂);3.99 (2H, t, J=8.5 Hz, indolyl CH₂); 3.06 (2H, t, J=8.5 Hz, indolylCH₂).

HPLC (Luna 2, Gradient 4): rt=2.55 minutes

LC/MS (Luna 2, Gradient 4): rt=1.98 minutes, 485 (MH)⁺.

Example 129 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-amido-2,3-dihydroindol-6-amide trifluoroacetate salt

A solution of 3-(N-BOC-aminomethyl)benzoyl-D/L-phenylglycine2,3-dihydroindolyl-6-amide (150 mg, 0.3 mmol) in anhydroustetrahydrofuran (5 mL) was treated under argon withtrimethylsilylisocyanate (81.2 μl, 0.6 mmol). The mixture was stirredovernight. The off-white precipitate was collected by filtration, anddissolved in dichloromethane (10 mL). The solution was treated withtrifluoroacetic acid (2 mL) for 4 hours until no starting materialremained by HPLC. The solvent was evaporated under reduced pressure, andtrituration of the residue with diethyl ether (3×20 mL) afforded thetitle compound as an off white solid (136 mg, 81.3%).

¹H NMR (d₆ DMSO): 10.32 ppm (1H, s); 8.84 (1H, d, J=8 Hz, Ar); 8.15 (2H,br s, NH₂); 8.02 (2H, d, J=12 Hz); 7.98 (1H, d, J=8 Hz, Ar); 7.63–7.31(8H, m, Ar); 7.03 (1H, d, J=8 Hz); 6.29 (2H, s, C(O)NH₂); 5.86 (1H, d,J=8 Hz, CHPh); 4.10 (2H, d, J=5 Hz, CH ₂NH₂); 3.85 (2H, t, J=8.5 Hz,indolyl CH₂); 3.03 (2H, t, J=8.5 Hz, indolyl CH₂).

HPLC (Luna 2, Gradient 4): rt=2.09 minutes

LC/MS (Luna 2, Gradient 4): rt=1.13 minutes, 444 (MH)⁺.

Example 130 3-(Aminomethyl)benzoyl-D/L-phenylglycine1-benzyl-2,3-dihydroindol-6-amide trifluoroacetate salt

To a stirred suspension of3-(N-BOC-aminomethyl)benzoyl-D/L-phenylglycine2,3-dihydroindolyl-6-amide (100 mg, 0.20 mmol) and sodium hydrogencarbonate (40 mg, 0.47 mmol) in DMF (10 mL) at room temperature wasadded a solution of benzyl bromide (60 μL, 85 mg, 0.5 mmol) in DMF (5mL). The mixture was heated at 65° C. for 1 hour and allowed to coolovernight. The solvent was removed under reduced pressure and theresidue partitioned between water (15 mL) and ethyl acetate (30 mL). Theorganic layer was dried over MgSO₄ and evaporated under reduced pressureto give a golden oil. The oil was dissolved in dichloromethane (20 mL)and treated with TFA (4 mL) overnight. The solvent was evaporated togive an oil, which was purified by preparative HPLC to give an off-whitesolid (57 mg, 47%).

¹H NMR (d₄ MeOH): 8.20 (2H, d, J=9 Hz, Ar); 7.81 (3H, m, Ar); 7.57 (9H,m, Ar); 7.27 (2H, m, Ar); 7.12 (1H, d, J=8 Hz, Ar); 6.03 (1H, s, CHPh);5.50 (2H, s, CH₂Ph); 4.41 (2H, s, CH ₂NH₂); 3.60 (2H, t, J=7.5 Hz,indoline C(2)H₂); 3.15 (2 H, t, J=7.5 Hz, indoline C(3)H₂).

HPLC (Luna 2, Gradient 4): rt=4.00 minutes.

HPLC (Symmetry, Gradient 2): rt=6.62 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.26 minutes, 491 (MH)⁺.

Example 131 3-(Aminomethyl)benzoyl-D/L-4-methylphenylglycineindan-5-amide hydrochloride salt N-Formyl-5-aminoindane

To a solution of 5-aminoindane (7.53 g, 56.5 mmol) in DMF (100 mL) wasadded formic acid (2.2 mL, 58.3 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.94 g, 57mmol) and diisopropylethylamine (19.7 mL, 0.11 mol). The resultingsolution was stirred overnight and then partitioned between saturatedaqueous citric acid (100 mL) and ethyl acetate (200 mL). The organiclayer was separated and washed with aqueous sodium bicarbonate solution(100 mL) and water (3×100 mL), then concentrated under reduced pressureto give the formamide as a thick oily solid (8.5 g, 93%).

Indan-5-isonitrile

To a solution of N-formyl-5-aminoindane (12 g, 74.5 mmol) indichloromethane (100 mL) was added triethylamine (23 mL, 0.17 mol) andthe solution was cooled to 0° C. under nitrogen. Phosphorous oxychloride(7 mL, 75 mmol) was added dropwise over 10 minutes, keeping thetemperature at 0° C. The mixture was stirred at this temperature for 1hour. A solution of sodium carbonate (15.6 g, 0.18 mol) in water (50 mL)was then added dropwise, keeping the temperature below 30° C. Themixture was diluted with water (100 mL) and then separated. The aqueouslayer was extracted with dichloromethane (2×50 mL) and the combinedorganic extracts then washed with brine (200 mL), dried over magnesiumsulphate and concentrated under reduced pressure. The crude oil waspurified by vacuum distillation to give the product as a clear oil whichsolidified at low temperature (7.8 g, 72%); bp. 100–105° C. (0.05 mBar).

¹H NMR (CDCl₃): 7.10 (4H, m, Ar); 2.82 (4H, t, J=8 Hz, C(1)H₂, C(3)H₂);2.03 (2H, quintet, J=8 Hz, C(2)H₂).

3-(BOC-aminomethyl)benzoyl-D/L-N-(2,4-dimethoxybenzyl)-4-methylphenylglycineindan-5-amide

A solution of p-tolualdehyde (168 mg, 1.4 mmol) and2,4-dimethoxybenzyl-amine (207 μL, 230 mg, 1.4 mmol) in dichloromethane(1 mL) was allowed to stand overnight. The solution was diluted to 5 mLwith dichloromethane and dried over magnesium sulfate. The solvent wasdecanted off, the solids rinsed with dichloromethane (2×1 mL) and thesolution diluted further to 10 mL. 3-(BOC-aminomethyl)benzoic acid (350mg, 1.4 mmol) and indane-5-isonitrile (4 mL of a 5 g/100 mL solution indichloromethane, 200 mg, 1.4 mmol) were added. The solution was stirredunder argon for 14 days before being evaporated under reduced pressureonto silica gel (5 g). Purification by Biotage Flash 40 chromatography,eluting with 2:1 to 1:1 hexane:ethyl acetate afforded3-(BOC-aminomethyl)benzoyl-D/L-N-(2,4-dimethoxybenzyl)-4-methylphenylglycineindan-5-amide as a white foamy solid (297 mg, 32%).

3-(Aminomethyl)benzoyl-D/L-4-methylphenylglycine indan-5-amidehydrochloride salt

A solution of3-(BOC-aminomethyl)benzoyl-D/L-N-(2,4-dimethoxybenzyl)-4-methylphenylglycineindan-5-amide (290 mg, 0.43 mmol) in dichlormethane (3 mL) was stirredat room temperature and trifluoroacetic acid (3 mL) was added. After 90minutes the excess trifluoroacetic acid and dichlormethane were removedunder reduced pressure. The purple oily residue was taken up in methanol(2 mL) and purified by SCX acid ion-exchange chromatography, elutingwith methanol and then 5%-10% 2 N NH₃/methanol in dichlormethane, toafford 3-(aminomethyl)benzoyl-D/L-4-methylphenylglycine indan-5-amide asits free base. This was taken up in acetonitrile (5 mL) and water (10mL) was added, followed by 5% HCl (aq.) to afford a pale yellowsolution. The acetonitrile was removed under reduced pressure and theaqueous solution was lyophilised to afford3-(aminomethyl)benzoyl-D/L-4-methylphenylglycine indan-5-amide as itshydrochloride salt (92 mg, 0.20 mmol, 48%).

¹H NMR (CD₃CN): 8.47 ppm (1H, br s, Ar); 7.72 (1H, s, Ar); 7.67–7.53(2H, m, Ar); 7.46–7.28 (4H, m, Ar); 7.13 (2H, d, J=10 Hz, tolyl C(2)H'sor C(3)H's); 7.07 (1H, d, J=10 Hz, indane C(6)H or C(7)H); 5.55 (1H, s,CHTol); 3.74 (2H, s, CH ₂NH₂); 2.81 (2H, t, J=6 Hz, indane C(1)H₂ orC(3)H₂); 2.77 (2H, t, J=6 Hz, indane C(1)H₂ or C(3)H₂); 2.27 (3H, s,CH₃Ar); 2.10–1.95 (2H, m, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.53 min.

LC/MS (Luna 2, Gradient 4): rt=2.13 min, 414 (MH)⁺.

Examples 132–146 were prepared in a similar manner, starting with theindicated aldehyde.

Example 132 3-(Aminomethyl)benzoyl-D/L-2-chlorophenylglycineindan-5-amide hydrochloride salt

From 2-chlorobenzaldehyde.

¹H NMR (d₆ DMSO): 10.27 ppm (1H, br s, C(O)NH-Indane); 9.08 (1H, br d,J=10 Hz, C(O)NHCHAr); 7.92 (1H, s, Ar); 7.78 (1H, d, J=10 Hz, Ar); 7.57(1H, s, Ar); 7.55–7.44 (3H, m, Ar); 7.42–7.30 (4H, m, Ar); 7.14 (1H, d,J=9 Hz, indane C(6)H or C(7)H); 6.07 (1H, d, J=10 Hz, C(O)NHCHAr); 4.11(2H, br s, CH₂NH ₂); 3.74 (2H, s, CH ₂NH₂); 2.83 (2H, t, J=6 Hz, indaneC(1)H₂ or C(3)H₂); 2.80 (2H, t, J=6 Hz, indane C(1)H₂ or C(3)H₂); 2.00(2H, quintet, J=6 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.46 min.

LC/MS (Luna 2, Gradient 4): rt=2.02 min, 434 (MH)⁺.

Example 133 3-(Aminomethyl)benzoyl-D/L-4-ethylphenylglycineindan-5-amide hydrochloride salt

From 4-ethylbenzaldehyde.

¹H NMR (d₆ DMSO): 10.30 ppm (1H, s, C(O)NH-Indane); 8.88 (1H, d, J=9 Hz,C(O)NHCHAr); 8.23 (3H, br s, NH₂ and Ar); 8.06 (1H, s, Ar); 7.99 (1H, d,J=9 Hz, Ar); 7.65 (1H, d, J=10 Hz, Ar); 7.55 (1H, s, Ar); 7.52 (2H, d,J=10 Hz, EtPh C(2)H's or C(3)H's); 7.34 (1H, d, J=10 Hz, indane C(6)H orC(7)H); 7.27 (2H, d, J=10 Hz, EtPh C(2)H's or C(3)H's); 7.15 (1H, d,J=10 Hz, indane C(6)H or C(7)H); 5.85 (1H, d, J=8 Hz, C(O)NHCHAr); 4.14(2H, s, CH ₂NH₂); 2.85 (2H, t, J=6 Hz, indane C(1)H₂ or C(3)H₂); 2.82(2H, t, J=6 Hz, indane C(1)H₂ or C(3)H₂); 2.63 (2H, q, J=9 Hz, CH ₂CH₃);2.01 (2H, quintet, J=6 Hz, indane C(2)H₂); 1.18 (3H, t, J=9 Hz, CH₂CH₃).

HPLC (Luna 2, Gradient 1): rt=4.77 min.

LC/MS (Luna 2, Gradient 4): rt=2.23 min, 428 (MH)⁺.

Example 134 3-(Aminomethyl)benzoyl-D/L-4-isopropylphenylglycineindan-5-amide hydrochloride salt

From 4-isopropylbenzaldehyde.

¹H NMR (CD₃CN): 8.53 ppm (1H, br s, NH); 7.78 (1H, s, Ar); 7.65 (2H, d,J=8 Hz, Ar); 7.48–7.30 (4H, m, Ar); 7.23 (2H, d, J=10 Hz, ^(i)PrPhC(2)H's or C(3)H's); 7.18 (1H, d, J=9 Hz, indane C(6)H or C(7)H); 7.08(1H, d, J=9 Hz, indane C(6)H or C(7)H); 5.58 (1H, d, J=7 Hz, CHAr); 3.78(2H, s, CH₂NH₂); 2.85 (1H, septet, J=9 Hz, CH(CH₃)₂); 2.79 (2H, t, J=6Hz, indane C(1)H₂ or C(3)H₂); 2.77 (2H, t, J=6 Hz, indane C(1)H₂ orC(3)H₂); 1.96 (2H, quintet, J=6 Hz, indane C(2)H₂); 1.17 (6H, d, J=9 Hz,CH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=4.96 min.

LC/MS (Luna 2, Gradient 4): rt=2.45 min, 442 (MH)⁺.

Example 135 3-(Aminomethyl)benzoyl-D/L-3-hydroxyphenylglycineindan-5-amide hydrochloride salt

From 3-hydroxybenzaldehyde.

¹H NMR (CD₃CN): 8.51 ppm (1H, br s, NH); 7.76 (1H, s, Ar); 7.70–7.58(2H, m, Ar); 7.46 (1H, d, J=9 Hz, Ar); 7.40–7.32 (2H, m, Ar and OH);7.20–7.15 (2H, m, Ar); 7.08 (1H, d, J=8 Hz, Ar); 7.00–6.92 (2H, m, Ar);6.73 (1H, d, J=9 Hz, Ar); 5.56 (1H, d, J=8 Hz, CHAr); 3.78 (2H, s, CH₂NH₂); 2.80 (2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 2.77 (2H, t, J=6Hz, indane C(1)H₂ or C(3)H₂); 1.98 (2H, quintet, J=6 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.01 min.

LC/MS (Luna 2, Gradient 4): rt=1.91 min, 416 (MH)⁺.

Example 136 3-(Aminomethyl)benzoyl-D/L-4-isopropoxyphenylglycineindan-5-amide hydrochloride salt

From 4-isopropoxybenzaldehyde.

¹H NMR (CD₃CN): 8.44 ppm (1H, br s, NH); 7.86 (1H, s, Ar); 7.64 (1H, d,J=10 Hz, Ar); 7.56 (1H, d, J=8 Hz, Ar); 7.50–7.30 (4H, m, Ar); 7.18 (1H,d, J=10 Hz, indane C(6)H or C(7)H); 7.09 (1H, d, J=10 Hz, indane C(6)Hor C(7)H); 6.86 (2H, d, J=10 Hz, ^(i)PrOPh C(2)H's or C(3)H's); 5.53(1H, d, J=8 Hz, CHAr); 4.54 (1H, septet, J=6 Hz, OCH(CH₃)₂); 3.77 (2H,s, CH ₂NH₂); 2.81 (2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 2.78 (2H, t,J=6 Hz, indane C(1)H₂ or C(3)H₂); 1.96 (2H, quintet, J=7 Hz, indaneC(2)H₂); 1.20 (6H, d, J=9 Hz, OCH(CH ₃)₂).

HPLC (Luna 2, Gradient 1): rt=4.83 min.

LC/MS (Luna 2, Gradient 4): rt=2.29 min, 458 (MH)⁺.

Example 137 3-(Aminomethyl)benzoyl-D/L-4-phenoxyphenylglycineindan-5-amide hydrochloride salt

From 4-phenoxybenzaldehyde.

¹H NMR (Free base, CDCl₃): 8.51 ppm (1H, br s, NH); 7.84 (1H, s, Ar);7.77 (1H, d, J=6 Hz, NHCHAr); 7.60–7.49 (2H, m, Ar); 7.48–7.38 (1H, m,Ar); 7.37–7.25 (4H, m, Ar); 7.22–7.09 (3H, m, Ar); 7.05–6.92 (4H, m,Ar); 6.10 (1H, d, J=8 Hz, CHAr); 3.95 (2H, s, CH ₂NH₂); 2.85 (4H, t, J=7Hz, indane C(1)H₂ and C(3)H₂); 2.07 (2H, quintet, J=7 Hz, indaneC(2)H₂); 1.52 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 1): rt=5.19 min.

LC/MS (Luna 2, Gradient 4): rt=2.48 min, 492 (MH)⁺.

Example 138 3-(Aminomethyl)benzoyl-D/L-2,4-dimethylphenylglycineindan-5-amide hydrochloride salt

From 2,4-dimethylbenzaldehyde.

¹H NMR (Free base, CDCl₃): 7.72 ppm (1H, s, Ar); 7.64 (1H, d, J=10 Hz,Ar); 7.45–7.25 (5H, m, Ar and NH); 7.09–7.02 (2H, m, Ar); 6.99 (2H, brs, Ar); 5.81 (1H, d, J=7 Hz, CHAr); 3.83 (2H, s, CH ₂NH₂); 2.83–2.71(4H, m, indane C(1)H₂ and C(3)H₂); 2.44 (3H, s, CH₃Ar); 2.25 (3H, s,CH₃Ar); 2.00 (2H, quintet, J=7 Hz, indane C(2)H₂); 1.40 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 1): rt=4.50 min.

LC/MS (Luna 2, Gradient 4): rt=2.10 min, 428 (MH)⁺.

Example 139 3-(Aminomethyl)benzoyl-D/L-2,5-dimethylphenylglycineindan-5-amide hydrochloride salt

From 2,5-dimethylbenzaldehyde.

¹H NMR (Free base, CDCl₃): 7.57 ppm (1H, s, Ar); 7.50 (1H, d, J=9 Hz,Ar); 7.30–7.13 (4H, m, Ar); 7.05 (1H, s, NH); 6.95–6.78 (4H, m, Ar);5.68 (1H, d, J=8 Hz, CHAr); 3.68 (2H, s, CH ₂NH₂); 2.70–2.55 (4H, m,indane C(1)H₂ and C(3)H₂); 2.27 (3H, s, CH₃Ar); 2.09 (3H, s, CH₃Ar);1.84 (2H, quintet, J=7 Hz, indane C(2)H₂); 1.27 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 1): rt=4.10 min.

LC/MS (Luna 2, Gradient 4): rt=1.99 min, 428 (MH)⁺.

Example 140 3-(Aminomethyl)benzoyl-D/L-6-methylpyridin-2-ylglycineindan-5-amide bis(hydrochloride) salt

From 6-methylpyridine-2-carboxaldehyde.

¹H NMR (Free base, CDCl₃): 9.70 ppm (1H, br s, NH-Indane); 8.27 (1H, d,J=7 Hz, NHCHAr); 7.97 (1H, s, Ar); 7.89 (1H, d, J=9 Hz, Ar); 7.67–7.48(4H, m, Ar); 7.27–7.10 (4H, m, Ar); 5.85 (1H, d, J=7 Hz, CHPy); 4.00(2H, s, CH ₂NH₂); 2.90 (2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 2.88(2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 2.66 (3H, s, CH₃Py); 2.09 (2H,quintet, J=7 Hz, indane C(2)H₂); 1.64 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 1): rt=3.28 min.

LC/MS (Luna 2, Gradient 4): rt=2.05 min, 415 (MH)⁺.

Example 141 3-(Aminomethyl)benzoyl-D/L-imidazol-4-ylglycineindan-5-amide bis(hydrochloride) salt

From imidazole-4-carboxaldehyde.

¹H NMR (Free base, CDCl₃): 9.90 ppm (1H, br s, NH-Indane); 8.39 (1H, brs, NH); 7.83 (1H, s, Ar); 7.72 (1H, d, J=9 Hz, Ar); 7.40 (2H, d, J=10Hz, Ar); 7.36–7.25 (2H, m, Ar); 7.24 (1H, d, J=8 Hz, indane C(6)H orC(7)H); 7.04 (1H, d, J=8 Hz, indane C(6)H or C(7)H); 6.93 (1H, s, Ar);6.02 (1H, br d, J=5 Hz, CH-Im); 3.78 (2H, s, CH ₂NH₂); 2.80 (2H, t, J=7Hz, indane C(1)H₂ or C(3)H₂); 2.78 (2H, t, J=7 Hz, indane C(1)H₂ orC(3)H₂); 2.00 (2H, quintet, J=7 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=3.65 min.

LC/MS (Luna 2, Gradient 4): rt=1.45 min, 390 (MH)⁺.

Example 142 3-(Aminomethyl)benzoyl-D/L-naphth-2-ylglycine indan-5-amidehydrochloride salt

From naphthalene-2-carboxaldehyde.

¹H NMR (Free base, CDCl₃): 8.52 ppm (1H, br s, NH); 7.97 (1H, s, Ar);7.80 (1H, d, J=8 Hz, Ar); 7.75 (1H, s, Ar); 7.69 (2H, d, J=10 Hz, Ar);7.66–7.55 (2H, m, Ar); 7.45 (1H, d, J=8 Hz, Ar); 7.41–7.29 (3H, m, Ar);7.26 (1H, s, Ar); 7.05 (1H, d, J=8 Hz, indane C(6)H or C(7)H); 6.95 (1H,d, J=8 Hz, indane C(6)H or C(7)H); 6.93 (1H, s, Ar); 6.19 (1H, d, J=9Hz, CH-Np); 4.35 (2H, s, CH ₂NH₂); 2.72 (2H, t, J=7 Hz, indane C(1)H₂ orC(3)H₂); 2.69 (2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 1.92 (2H,quintet, J=7 Hz, indane C(2)H₂); 1.55 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 4): rt=2.80 min.

LC/MS (Luna 2, Gradient 4): rt=2.29 min, 450 (MH)⁺.

Example 143 3-(Aminomethyl)benzoyl-D/L-1,3-benzodioxazol-5-ylglycineindan-5-amide hydrochloride salt

From piperonal.

¹H NMR (Free base, CDCl₃): 9.32 ppm (1H, br s, NH); 7.97 (1H, d, J=9 Hz,Ar); 7.79 (1H, s, Ar); 7.75 (1H, d, J=10 Hz, Ar); 7.47 (1H, d, J=8 Hz,Ar); 7.41–7.30 (2H, m, Ar); 7.08–6.98 (2H, m, Ar); 6.68 (1H, d, J=10 Hz,Ar); 6.16 (1H, d, J=8 Hz, CH-Np); 5.85 (2H, d, J=11 Hz, OCH₂O); 3.84(2H, s, CH ₂NH₂); 2.80 (2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 2.76(2H, t, J=7 Hz, indane C(1)H₂ or C(3)H₂); 2.00 (2H, quintet, J=7 Hz,indane C(2)H₂); 1.85 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 4): rt=2.59 min.

LC/MS (Luna 2, Gradient 4): rt=2.13 min, 444 (MH)⁺.

Example 144 3-(Aminomethyl)benzoyl-D/L-5-methylfuran-2-ylglycineindan-5-amide hydrochloride salt

From 5-methylfuran-2-carboxaldehyde.

¹H NMR (Free base, CDCl₃): 9.02 ppm (1H, br s, NH); 7.78 (2H, br s, NHand Ar); 7.65 (1H, d, J=9 Hz, Ar); 7.39 (1H, s, Ar); 7.37 (1H, d, J=8Hz, Ar); 7.28 (1H, t, J=7 Hz, 3-aminomethylphenyl C(5)H); 7.19 (1H, d,J=10 Hz, Ar); 7.00 (1H, d, J=9 Hz, indane C(6)H or C(7)H); 6.29 (1H, d,J=3 Hz, furyl C(3)H or C(4)H); 6.15 (1H, d, J=8 Hz, CH-Fur); 5.79 (1H,d, J=3 Hz, furyl C(3)H or C(4)H); 3.82 (2H, s, CH₂NH₂); 2.75 (2H, t, J=7Hz, indane C(1)H₂ or C(3)H₂); 2.72 (2H, t, J=7 Hz, indane C(1)H₂ orC(3)H₂); 2.40 (2H, br s, NH₂); 2.10 (3H, s, CH₃-Fur); 1.93 (2H, quintet,J=7 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=4.09 min.

LC/MS (Luna 2, Gradient 4): rt=2.05 min, 404 (MH)⁺.

Example 145 3-(Aminomethyl)benzoyl-D/L-benzofuran-2-ylglycineindan-5-amide hydrochloride salt

From benzofuran-2-carboxaldehyde.

¹H NMR (Free base, CDCl₃): 9.27 ppm (1H, br s, NH); 7.96 (1H, d, J=8 Hz,NHCHAr); 7.72 (1H, s, Ar); 7.66 (1H, d, J=9 Hz, Ar); 7.40–7.23 (5H, m,Ar); 7.18–7.04 (2H, m, Ar); 6.97 (1H, d, J=8 Hz, Ar); 6.92 (1H, d, J=9Hz, indane C(6)H or C(7)H); 6.76 (1H, s, benzofuran C(3)H); 6.45 (1H, d,J=8 Hz, CHAr); 3.76 (2H, s, CH ₂NH₂); 2.77–2.60 (4H, m, indane C(1)H₂and C(3)H₂); 2.10 (3H, s, CH₃-Fur); 2.01–1.89 (2H, m, indane C(2)H₂);1.64 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 1): rt=4.13 min.

LC/MS (Luna 2, Gradient 4): rt=2.15 min, 440 (MH)⁺.

Example 146 3-(Aminomethyl)benzoyl-D/L-3-methylbenzo (b)thiophen-2-ylglycine indan-5-amide hydrochloride salt

From 3-methylbenzo(b)thiophene-2-carboxaldehyde.

¹H NMR (Free base, CDCl₃): 8.39 ppm (1H, br s, NH); 7.74–7.62 (4H, m, NHand Ar); 7.58 (1H, d, J=8 Hz, Ar); 7.38 (1 H, d, J=9 Hz, Ar); 7.35–7.23(4H, m, Ar); 7.09 (1H, d, J=10 Hz, indane C(6)H or C(7)H); 6.99 (1H, d,J=10 Hz, indane C(6)H or C(7)H); 6.40 (1H, d, J=8 Hz, CHAr); 3.79 (2H,s, CH ₂NH₂); 2.75 (2H, t, J=6 Hz, indane C(1)H₂ or C(3)H₂); 2.73 (2H, t,J=6 Hz, indane C(1)H₂ or C(3)H₂); 2.50 (3H, s, CH ₃Ar); 2.00–1.88 (2H,m, indane C(2)H₂); 1.55 (2H, br s, NH₂).

HPLC (Luna 2, Gradient 1): rt=4.33 min.

LC/MS (Luna 2, Gradient 4): rt=2.34 min, 470 (MH)⁺.

Example 147 3-(Aminomethyl)benzoyl-D/L-(4-hydroxycarbonyl)-phenylglycineindan-5-amide trifluoroacetate salt3-(BOC-aminomethyl)benzoyl-D/L-N-(2,4-dimethoxybenzyl)-4-(methoxycarbonyl)phenylglycineindan-5-amide

4-Methoxycarbonylbenzaldehyde was reacted in the same way asp-tolualdehyde in Example 131, to afford3-(N-BOC-aminomethyl)benzoyl-D/L-N-(2,4-dimethoxybenzyl)-4-(methoxycarbonyl)phenylglycineindan-5-amide.

3-(BOC-aminomethyl)benzoyl-D/L-N-(2,4-dimethoxybenzyl)-4-(hydroxycarbonyl)phenylglycineindan-5-amide

To a stirred solution of the methyl ester (0.55 g, 0.77 mmol) in 1:1THF/water (30 mL) was added lithium hydroxide monohydrate (65 mg, 1.5mmol). The solution was warmed to 70° C. for 2 hours, then cooled toroom temperature overnight. The reaction mixture was acidified with 5%aqueous HCl and extracted with ethyl acetate (2×100 mL). The driedextracts were evaporated to give an oily foam.

Trifluoroacetic acid (4 mL) was added to a stirred solution of the foam(40 mg) in dichloromethane (20 mL) and allowed to stand overnight,resulting in the solution turning deep pink. The solution was evaporatedto give a reddish oil which was triturated with ether to give a greysolid, which was purified by preparative HPLC to give a white solid (34mg, 8%).

3-(Aminomethyl)benzoyl-D/L-4-(hydroxycarbonyl)phenyl-glycineindan-5-amide trifluoroacetate salt

¹H NMR (d₄ MeOH): 8.13 ppm (2H, d, J=9 Hz, Ar); 8.03 (2H, s, Ar);7.81–7.62 (4H, m, Ar); 7.34 (1H, dd, J=9, 5 Hz, Ar); 7.20 (1H, d, J=8Hz, Ar); 5.97 (1H, s, CHPh); 4.25 (1H, s, CH₂NH₂); 2.92 (4H, m, indaneC(1)H₂ and C(3)H₂); 2.12 (quintet, J=7 Hz, indane C(2)H₂).

HPLC (Luna 2, Gradient 1): rt=3.64 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 445 (MH)⁺.

Example 148 3-(Aminomethyl)benzoyl-D/L-(4-hydroxymethyl)phenylglycineindan-5-amide trifluoroacetate salt

To a stirred solution of3-(BOC-aminomethyl)benzoyl-D/L-N-2,4-dimethoxybenzyl-(4-hydroxycarbonyl)phenylglycineindan-5-amide (0.49 g, 0.71 mmol) in THF (15 mL) at 0° C. was added 1.0Mborane/THF complex (5 mL, 5 mmol) dropwise, then left for 2 hrs. To theresulting solution was added 1:1 acetic acid/water (10 mL), leftovernight, then evaporated under reduced pressure. The resulting slushysolid was partitioned between water (30 mL) and ethyl acetate (50 mL).The organic layer was dried over MgSO₄ and evaporated to give anoff-white foam. The foam was dissolved in dichloromethane (20 mL) andtreated with trifluoroacetic acid (4 mL) for 4 hours, then evaporated togive an oil. The oil was purified by preparative HPLC to give a whitesolid (100 mg, 30%).

¹H NMR (d₄ MeOH): 7.90 (2H, m, Ar); 7.62–7.49 (4H, m, Ar); 7.35 (3H, m,Ar); 7.18 (1H, d, J=8 Hz, Ar); 7.08 (1H, d, J=8 Hz, Ar); 5.78 (1H, s,CHPh); 4.57 (2H, s, CH₂OH); 4.13 (1H, s, CH₂NH₂); 2.83 (1H, m, J=7 Hz,2× indane CH₂); 2.02 (2H, quintet, J=7 Hz, indane CH₂).

HPLC (Luna 2, Gradient 1): rt=3.78 minutes.

HPLC (Symmetry, Gradient 2): rt=5.89 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.88 minutes, 430 (MH)⁺.

Example 149 3-(Aminomethyl)benzoyl-D/L-2-phenylthiazol-4-ylglycineindan-5-amide trifluoroacetate salt

Prepared in a similar manner to Example 61 except thatα-N-BOC-D/L-2-phenylthiazol-4-ylglycine, synthesised as described below,was used in place ofD/L-4-(N-BOC-aminomethyl)-α-(N-benzyloxycarbonyl)phenylglycine.

Ethyl oximinoacetoacetate

This was prepared from ethyl acetoacetate (10.00 g) using the method ofFischer (Organic Synthesis Coll. Vol. 3, 513–516) to yield the titledcompound (12.45 g).

¹H NMR (CDCl₃) 1.25 (3H, t), 2.35 (3H, s), 4.3 (2H, q), 8.8 (1H, br.).

Ethyl-γ-chloro-α-oximinoacetoacetate

This was prepared from ethyl oximinoacetoacetate (1.73 g) using themethod of Hatanaka et al. (Journal of Medicinal Chemistry, 1973, 16(9),978–984) to yield the titled compound (1.44 g).

¹H NMR (CDCl₃) 1.25 (3H, t), 4.3 (2H, q), 4.55 (2H, s), 9.45 (1H, s),contains 20% starting material by NMR.

N-BOC-D/L-2-phenylthiazol-4-ylglycine

A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.10 g, 10.8 mmol)and thiobenzamide (1.49 g, 10.8 mmol) in dry benzene (15 mL) was heatedto reflux. After 4 hours, the reaction mixture was poured onto NaHCO₃(sat., aq., 50 mL); The resulting mixture was extracted with ethylacetate (2×50 mL); and the combined extracts dried over MgSO₄ andevaporated under reduced pressure. Flash chromatography (ethylacetate:hexane 1:4, R_(f) 0.30) then afforded impure ethylα-oximino-2-phenylthiazole-4-acetate (3.22 g). The crude oxime was thendissolved in methanol (15 mL) and formic acid (50% aq., 15 mL) wasadded. The mixture was cooled to 0° C. and zinc dust (2.00 g, 30.6 mmol)was added portionwise over 30 minutes. The reaction mixture was allowedto warm to room temperature, and stirred for 6 hours. The solution wasthen filtered, basified to pH 9 with solid NaHCO₃, and extracted withethyl acetate (3×80 mL). The combined extracts were then dried andevaporated to afford D/L-2-phenylthiazol-4-ylglycine ethyl ester (1.43g, 5.45 mmol, 50% from the chloro-oxime). The ester (194 mg, 0.74 mmol)was then dissolved in tetrahydrofuran (5 mL). Triethylamine (120 μL, 87mg, 0.86 mmol) was added, followed by di-t-butyl dicarbonate (180 mg,0.82 mmol). After stirring at room temperature for 4 days, water (20 mL)was added and the solution extracted with dichloromethane (2×20 mL). Thecombined extracts were evaporated and purified by flash columnchromatography (ethyl acetate:hexane 1:4, R_(f) 0.45) to affordN-t-butyloxycarbonyl-D/L-2-phenylthiazol-4-ylglycine ethyl ester (158mg, 0.44 mmol, 59%) as a clear oil. The oil was dissolved intetrahydrofuran (2 mL) and LiOH.H₂O (80 mg as a solution in 2 mL water)was added. After stirring at room temperature for 2 hours, water (10 mL)was added, and the solution extracted with ethyl acetate (5 mL). Theaqueous layer was then acidified to pH 4 with 2N HCl, and extracted withethyl acetate (2×20 mL); The latter extracts were combined andevaporated to afford N-BOC-D/L-2-phenylthiazol-4-ylglycine (116 mg, 0.35mmol, 75%) as a white powder.

¹H NMR (CDCl₃): 10.81 (1H, br s, CO₂ H); 7.80–7.71 & 7.30–7.22 (2H & 3H,m, Ph); 7.21 (1H, s, thiazole CH); 5.99 (1H, br d, J=6 Hz, NHBoc); 5.39(1H, br d, J=6 Hz, α-CH); 1.31 (9H, s, C(CH ₃)₃).

3-(Aminomethyl)benzoyl-D/L-2-phenylthiazol-4-ylglycine indan-5-amidetrifluoroacetate salt

¹H NMR (d₃ acetonitrile): 9.00 (1H, s, NHAr); 8.15 (1H, d, J=6 Hz,NHCH); 8.02 (1H, s, Ar); 7.99–7.88 (2H, m, Ar); 7.59–7.40 (7H, m, Ar);7.25 & 7.11 (2×1H, 2×d, 2×J 7 Hz, indanyl CHCH); 6.01 (1H, d, J=6 Hz);4.15 (2H, br s, CH ₂NH₂); 2.90–2.79 (4H, m, CH ₂CH₂CH ₂); 2.00 (2H,pentet, J=6 Hz, CH₂CH ₂CH₂).

HPLC (Luna 2, Gradient 1): rt=4.22 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.29 minutes, 483 (MH)⁺.

Example 150 3-(Aminomethyl)benzoyl-D/L-(2-methylthiazol-4-yl)glycineindan-5-amide trifluoroacetate salt

Synthesised from N-BOC-D/L-2-methylthiazol-4-ylglycine, which wasprepared in an analogous manner to N-BOC-D/L-2-phenylthiazol-4-ylglycineabove, except that thioacetamide was used in place of thiobenzamide.

¹H NMR (d₄ MeOH): 8.00 ppm (2H, m, Ar); 7.8–7.57 (2H, m, Ar); 7.48 (2H,d, J=8 Hz, Ar); 7.30 (1H, d, J=9 Hz, Ar); 7.16 (1H, d, J=8 Hz, Ar); 6.01(1H, s, CHPh); 4.21 (2H, s, CH ₂NH₂); 2.90 (2H, t, J=8 Hz, indane C(1)H₂or C(3)H₂); 2.88 (2H, t, J=8 Hz, indane C(1)H₂ or C(3)H₂); 2.74 (3H, s,Me); 2.10 (2H, quintet, J=8 Hz, indane C(2)H₂).

HPLC (Luna, Gradient 3): rt=5.92 (92%)

LC/MS (Luna 2, Gradient 4): rt=1.88 minutes, 421 (MH)⁺.

Example 151 3-(Aminomethyl)benzoyl-D/L-(4-aminocarbonyl)phenylglycineindan-5-amide trifluoroacetate salt3-(N-BOC-Aminomethyl)benzoyl-D/L-(4-methoxycarbonyl)phenylglycineindan-5-amide

Prepared in a manner analogous to the preparation of3-(N-BOC-aminomethyl)benzoyl-D/L-4-(N-BOC-aminomethyl)phenylglycineindan-5-amide, an intermediate in the preparation of Example 61, exceptthat α-N-BOC-D/L-(4-methoxycarbonyl)phenylglycine was used instead ofα-N-Z-D/L-(4-BOC-aminomethyl)phenylglycine; appropriate deprotectionmethods were used where required.

3-(N-BOC-Aminomethyl)benzoyl-D/L-(4-hydroxycarbonyl)phenylglycineindan-5-amide

A solution of the methyl ester (500 mg, 0.90 mmol) in tetrahydrofuran(15 mL) was treated with a solution of LiOH in water (1 mL of 1M, 1.0mmol) and the mixture heated at reflux for three hours. After cooling toroom temperature, the solution was diluted with water (50 mL), madeacidic with 1N HCl and extracted with ethyl acetate (3×15 mL). Thesolvents were dried over MgSO₄ and evaporated under reduced pressure toafford the acid as an off-white solid (390 mg, 80%) which was usedwithout further purification.

3-(N-BOC-Aminomethyl)benzoyl-D/L-(4-aminocarbonyl)phenylglycineindan-5-amide

A solution of3-(N-BOC-aminomethyl)benzoyl-D/L-(4-hydroxycarbonyl)phenylglycineindan-5-amide (370 mg, 0.7 mmol) in chloroform (10 mL) was treated withEEDQ (210 mg, 0.85 mmol) and NH₄HCO₃ (150 mg, 1.9 mmol) and stirredovernight at room temperature. The organic phase was washed with water(3×10 mL), dried (MgSO₄) and concentrated under reduced pressure. Theresidue was purified by flash chromatography using ethylacetate/chloroform 1/1 as eluant to afford the carboxamide as acolourless solid (52 mg, 14%).

¹H NMR (CDCl₃): 9.30 ppm (1H, s, NH); 8.85 (2H, s, NH₂); 8.10–7.98 (2H,m, Ar); 7.81–7.25 (8H, m, Ar and NH); 7.10 (1H, d, J=7.2 Hz, Ar); 6.98(1H, d, J=7.2 Hz, Ar); 6.14 (1H, s, CHPh); 5.00 (1H, br s, NH); 4.22(2H, s, CH ₂NH₂); 2.79–2.63 (4H, m, 2×CH₂ indane); 2.00–1.88 (2H, m, CH₂indane); 1.37 (9H, s, C₄H₉).

3-(Aminomethyl)benzoyl-D/L-(4-aminocarbonyl)phenylglycine indan-5-amidetrifluoroacetate salt

A solution of3-(N-BOC-aminomethyl)benzoyl-D/L-(4-aminocarbonyl)phenylglycineindan-5-amide (26 mg, 0.05 mmol) in dichloromethane (3 mL) was stirredat room temperature and trifluoroacetic acid (2 mL) was added. Stirringwas continued for a further hour and the solvents were removed underreduced pressure. The TFA salt was purified by flash chromatographyusing methanol/chloroform 1/4as eluant to afford a colourless solid (20mg, 91%).

¹H NMR (d₄ methanol): 7.86–7.72 ppm (3H, m, Ar); 7.67 (1H, d, J=7.2 Hz,Ar); 7.57 (2H, d, J=7.2 Hz, Ar); 7.40 (1H, d, J=7.2 Hz, Ar); 7.34–7.27(2H, m, Ar); 7.13 (1H, d, J=7.2 Hz, Ar); 7.00 (1H, d, J=7.2 Hz, Ar);5.79 (1H, s, CHPh); 3.77 (2H, s, CH ₂NH₂); 2.83–2.67 (4H, m, 2×CH₂indane); 2.03–1.91 (2H, m, CH₂ indane).

HPLC (Luna 2, Gradient 1): rt=1.75 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.83 minutes, 443 (MH)⁺.

Example 152 3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine1-(aminopropionyl)-2,3-dihydroindol-6-amide tris(hydrochloride) salt

Prepared in a manner analogous to that of Example 61, except that1-(3-N-BOC-aminopropyl)-6-amino-2,3-dihydroindole, synthesised asdescribed below, was used in place of 5-aminoindane.

1-(3-N-BOC-Aminopropyl)-6-nitro-2,3-dihydroindole

To a solution of N-BOC-β-alanine (1.15 g, 6.1 mmol) and6-nitro-2,3-dihydroindole (1.0 g, 6.1 mmol) in DMF (20 mL) was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.7mmol) and diisopropylethylamine (1.17 mL, 6.7 mmol). The resultingsolution was stirred overnight at room temperature. After this time themixture was partitioned between saturated aqueous citric acid (50 mL)and ethyl acetate (100 mL). The organic layer was separated and washedsuccessively with saturated aqueous sodium bicarbonate solution (50 mL)and water (3×50 mL), dried over MgSO₄, and then concentrated underreduced pressure to give the product as a pale foam (1.49 g, 76%).

¹H NMR (CDCl₃): 8.98 ppm (1H, d, J=1 Hz, C(7)H); 7.82 (1H, dd, J=10, 1Hz, C(5)H); 7.21 (1H, d, J=10 Hz, C(4)H); 5.33 (1H, br s, NH); 4.07 (2H,t, J=8 Hz, C(2)H₂); 3.48 (2H, m, CH₂CH ₂NHBoc); 3.22 (2H, t, J=8 Hz,C(3)H₂); 2.60 (2H, t, J=5 Hz, CH ₂CH₂NHBoc; 1.38 (9H, s, ^(t)Bu).

1-(3-N-BOC-aminopropyl)-6-amino-2,3-dihydroindole

To a solution of 1-(3-BOC-aminopropyl)-6-nitro-2,3-dihydroindole (1.49g, 4.7 mmol) in methanol (40 mL) was added 10% palladium on carbon(catalytic ammount) and the resulting suspension stirred vigorouslyunder an atmosphere of hydrogen. After 3 hours the mixture was purgedwith nitrogen and filtered through celite to remove the catalyst. Thefiltrate was concentrated under reduced pressure to give the product asa pale solid (1.35 g, quantitative).

¹H NMR (CDCl₃): 7.68 ppm (1H, d, J=1 Hz, C(7)H); 6.95 (1H, d, J=10 Hz,C(4)H); 6.39 (1H, dd, J=10, 1 Hz, C(5)H); 5.31 (1H, br s, NH); 4.0 (2H,t, J=8 Hz, C(2)H₂), 3.50 (2H, m, CH₂CH ₂NHBoc); 3.06 (2H, J=8 Hz,C(5)H₂); 2.99 (2H, br s, NH₂); 2.61 (2H, t, J=5 Hz, CH ₂CH₂NHBoc); 1.42(9H, s, ^(t)Bu).

3-(Aminomethyl)benzoyl-D/L-4-(aminomethyl)phenylglycine1-(aminopropionyl)-2,3-dihydroindol-6-amide tris(hydrochloride) salt

¹H NMR (D₂O): 7.91 ppm (1H, s, Ar); 7.66 (2H, br s, Ar); 7.50–7.46 (1H,m, Ar); 7.43 (2H, d, J=10 Hz, p-aminomethylphenyl C(2)H's or C(3)H's);7.37 (1H, d, J=10 Hz, Ar); 7.30 (2H, d, J=10 Hz, p-aminomethylphenylC(2)H's or C(3)H's); 7.02 (1H, d, J=9 Hz, indoline C(4)H or C(5)H); 6.86(1H, d, J=9 Hz, indoline C(4)H or C(5)H); 5.54 (1H, s, CHAr); 4.01 (2H,s, ArCH ₂NH₂); 3.97 (2H, s, ArCH ₂NH₂); 3.82 (2H, t, J=9 Hz, CH₂CH₂NH₂); 3.10 (2H, t, J=6 Hz, indoline C(2)H₂); 2.90 (2H, t, J=9 Hz, CH₂CH₂NH₂); 2.66 (2H, t, J=6 Hz, indoline C(3)H₂).

HPLC (Luna 2, Gradient 4): rt=1.42 min.

LC/MS (Luna 2, Gradient 4): rt=0.86 min, 501 (MH)⁺.

Example 153 3-(Aminomethyl)benzoyl-D/L-piperidin-4-ylglycine4-isopropylanilide

Prepared in a manner analogous to Example 69, except that4-isopropylaniline was used in place of 5-aminoindane.

¹H NMR (d₄ methanol): 8.04–7.93 ppm (2H, m, Ar); 7.73–7.50 (4H, m, Ar);7.20 (2H, d, J=7.5 Hz, Ar); 4.67 (1H, d, J=7.5 Hz, CH); 4.19 (2H, s, CH₂NH₂); 3.56–3.41 (2H, m, CH₂ pip); 3.12–2.97 (2H, m, CH₂ pip); 2.87 (1H,quintet, CH ipr); 2.44–2.26 (1H, m, Ar); 2.22–1.98 (2H, m, CH₂ pip);1.87–1.58 (2H, m, CH₂ pip); 1.28–1.21 (6H, app. d, 2×CH₃).

HPLC (Luna 2, Gradient 1): rt=2.18 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.37 minutes, 409 (MH)⁺.

Example 154 3-(Aminomethyl)benzoyl-D/L-piperidin-4-ylglycine1-acetyl-2,3-dihydroindol-6-amide bis(trifluoroacetate) salt

Prepared in a manner analogous to Example 69 except that1-acetyl-2,3-dihydroindol-6-amine was used in place of 5-aminoindane.

¹H NMR (d₆ DMSO): 8.65 ppm (1H, br s, NH); 8.34–8.17 (3H, m, NH); 8.00(1H, s, Ar); 7.93 (1H, d, J=7.5 Hz, Ar); 7.63 (1H, d, J=7.2 Hz, Ar);7.55–7.46 (3H, m, Ar); 7.15 (1H, d, J=7.5 Hz, Ar); 4.58 (1H, d, J=7.5Hz, CH); 4.14–4.01 (4H, m, CH ₂NH₂, CH₂ indoline); 3.40–3.27 (2H, m, CH₂pip); 3.15–3.02 (2H, m, CH₂ indoline); 2.96–2.73 (2H, m, CH₂ pip); 2.16(3H, s, COCH₃); 2.02–1.89 (1H, m, CH pip); 1.80–1.68 (1H, m, CH pip);1.64–1.33 (3H, m, CH, CH₂ pip).

HPLC (Luna 2, Gradient 1): rt=2.65 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.54 minutes, 450 (MH)⁺.

Example 155 3-(Aminomethyl)benzoyl-D/L-piperidin-4-glycine1-(aminoacetyl)-2,3-dihydroindol-6-amide tris(trifluoroacetate) salt

Prepared in a manner analogous to Example 69 except that1-(N-BOC-aminoacetyl)-2,3-dihydroindol-6-amine was used in place of5-aminoindane.

¹H NMR (d₄ methanol): 8.46 ppm (1H, s, Ar); 8.03–7.91 (2H, m, Ar); 7.70(1H, d, J=7.2 Hz, Ar); 7.65–7.54 (1H, m, Ar); 7.40 (1H, d, J=7.5 Hz,Ar); 7.21 (1H, d, J=7.5 Hz, Ar); 4.65 (1H, d, J=7.5 Hz, CH); 4.21 (2H,s, CH ₂NH₂); 4.16–4.07 (2H, m, CH₂ indoline); 4.02 (2H, s, CH ₂NH₂);3.55–3.40 (2H, m, CH₂ pip); 3.28–3.17 (2H, m, CH₂ indoline); 3.10–2.92(2H, m, CH₂ pip); 2.40–2.25 (1H, m, CH pip); 2.23–1.93 (2H, m, CH₂ pip);1.86–1.60 (2H, m, CH₂ pip).

HPLC (Luna 2, Gradient 1): rt=2.03 minutes.

LC/MS (Luna 2, Gradient 4): rt=0.64 minutes, 465 (MH)⁺.

Example 156 3-(Aminomethyl)benzoyl-D/L-1-acetylpiperidin-4-ylglycineindan-5-amide trifluoroacetate salt3-(N-Z-Aminomethyl)benzoyl-D/L-1-BOC-piperidin-4-ylglycine indan-5-amide

This compound was prepared in an analogous fashion to3-(N-BOC-aminomethyl)benzoyl-D/L-(N-BOC-piperidin-4-yl)glycineindan-5-amide, an intermediate in the synthesis of Example 69, exceptthat 3-(N-Z-aminomethyl)benzoic acid was used in the final couplingreaction.

3-(N-Z-Aminomethyl)benzoyl-D/L-1-acetylpiperidin-4-ylglycineindan-5-amide

A solution of 3-(N-Z-aminomethyl)benzoyl-D/L-1-BOC-piperidin-4-ylglycineindan-5-amide (65 mg, 0.1 mmol) in dichloromethane (3 mL) was stirred atroom temperature and trifluoroacetic acid (2 mL) was added. Stirring wascontinued for an hour and the solvents were removed under reducedpressure. The residue was taken up in dichloromethane (5 mL) and treatedwith triethylamine (0.055 mL, 0.4 mmol) and acetyl chloride (0.014 mL,0.2 mmol) and allowed to stir for 1 hour. The solution was washed withwater (3×5 mL), dried (MgSO₄) and concentrated under reduced pressure.The residue was purified by flash chromatography usingmethanol/dichloromethane 1/9 as eluent to afford a colourless solid (45mg, 78%).

¹H NMR (d₄ methanol): 7.82–7.68 ppm (2H, m, Ar); 7.51–7.20 (9H, m, Ar);7.16 (1H, d, J=7.2 Hz, Ar); 5.09 (2H, s, OCH₂Ph); 4.65–4.47 (2H, m, CHand NH); 4.31 (2H, s, CH ₂NH₂); 4.00–3.85 (1H, m, CH pip); 3.14–2.97(1H, m, CH pip); 2.92–2.77 (4H, m, 2×CH₂ indane); 2.66–2.48 (1H, m, CHpip); 2.32–2.17 (1H, m, CH pip); 2.15–1.90 (6H, m, COCH₃, CH₂ ind, CHpip); 1.85–1.67 (1H, m, CH pip); 1.53–1.20 (2H, m, CH₂ pip).

3-(Aminomethyl)benzoyl-D/L-1-acetylpiperidin-4-ylglycine indan-5-amidetrifluoroacetate salt

10% Palladium on carbon (20 mg) was added to a solution of3-(N-Carbobenzyloxy-aminomethyl)benzoyl-D/L-1-acetylpiperidin-4-ylglycineindan-5-amide (45 mg, 0.08 mmol) in methanol (20 mL) and the suspensionwas stirred under a hydrogen atmosphere overnight. The mixture wasfiltered and the filter was washed with methanol (20 mL). The combinedfiltrates were concentrated under reduced pressure and the amine waspurified by flash chromatography using methanol/dichloromethane 1/9 aseluant to afford a colourless solid. Trifluoroacetic acid (1 mL) wasadded and the solution was concentrated under reduced pressure to givethe TFA salt (16 mg, 36%).

¹H NMR (d₄ methanol): 7.98–7.87 ppm (2H, m, Ar); 7.73–7.20 (4H, m, Ar);7.10 (1H, d, J=7.2 Hz, Ar); 4.55 (1H, s, CH); 4.15 (2H, s, CH ₂NH₂);4.00–3.82 (2H, m, CH₂ pip); 3.15–2.95 (1H, m, CH pip); 2.89–2.71 (4H, m,2×CH₂ indane); 2.66–2.48 (1H, m, CH pip); 2.29–2.11 (1H, m, CH pip);2.10–1.85 (6H, m, COCH₃, CH₂ ind, CH pip); 1.81–1.62 (1H, m, CH pip);1.50–1.19 (2H, m, CH₂ pip).

HPLC (Luna 2, Gradient 1): rt=3.64 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.75 minutes, 449 (MH)⁺.

Examples 157–159 were prepared in a manner analogous to Example 156,except that the indicated carboxylic acid derivative was used to formthe amide of the piperidine nitrogen, under appropriate conditions.

Example 1573-(Aminomethyl)benzoyl-D/L-(1-propanoyl)piperidin-4-ylglycineindan-5-amide trifluoroacetate salt

From propanoyl chloride.

¹H NMR (d₄ methanol): 7.80 ppm (2H, s, Ar); 7.59–7.41 (2H, m, Ar); 7.36(1H, s, Ar); 7.16 (1H, d, J=7.2 Hz, Ar); 7.03 (1H, d, J=7.2 Hz, Ar);4.53–4.39 (2H, m, CH, CH pip); 4.04 (2H, s, CH ₂NH₂); 3.07–2.90 (1H, m,CH pip); 2.86–2.70 (4H, m, 2×CH₂ ind); 2.61–2.43 (1H, m, CH pip);2.36–2.22 (2H, m, COCH ₂CH₃); 2.19–2.04 (1H, m, CH pip); 2.01–1.79 (3H,m, CH₂ ind, CH pip); 1.76–1.60 (1H, m, CH pip); 1.41–1.10 (2H, m, CH₂pip); 0.93 (3H, t, J=7.5 Hz, COCH₂CH ₃).

HPLC (Luna 2, Gradient 1): rt=3.54 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.96 minutes, 463 (MH)⁺.

Example 1583-(Aminomethyl)benzoyl-D/L-(1-isobutyryl)piperidin-4-ylglycineindan-5-amide

From isobutyryl chloride.

¹H NMR (d₄ methanol): 7.75 ppm (1H, s, Ar); 7.67 (1H, d, J=7.2 Hz, Ar);7.42 (1H, d, J=7.2 Hz, Ar); 7.38–7.29 (2H, m, Ar); 7.18 (1H, d, J=7.5Hz, Ar); 7.03 (1H, d, J=7.5 Hz, Ar); 4.57–4.41 (1H, m, CH); 4.09–3.95(1H, m, CH pip); 3.81 (2H, s, CH ₂NH₂); 3.10–2.94 (1H, m, CH pip);2.91–2.67 (5H, m, CH ipr, 2×CH₂ ind); 2.62–2.43 (1H, m, CH pip);2.25–2.07 (1H, m, CH pip); 2.04–1.59 (4H, m, CH₂ ind, 2×CH pip);1.43–1.12 (2H, m, CH₂ pip); 0.98 (6H, m, 2×CH₃).

HPLC (Luna 2, Gradient 1): rt=3.39 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.88 minutes, 477 (MH)⁺.

Example 1593-(Aminomethyl)benzoyl-D/L-(1-aminoacetyl)piperidin-4-ylglycineindan-5-amide bis(trifluoroacetate) salt

From N-BOC-glycine.

¹H NMR (d₄ methanol): 7.94–7.81 ppm (2H, m, Ar); 7.58 (1H, d, J=7.2 Hz,Ar); 7.54–7.44 (1H, m, Ar); 7.38 (11H, s, Ar); 7.20 (1H, d, J=7.5 Hz,Ar); 7.08 (1H, d, J=7.2 Hz, Ar); 4.54–4.40 (1H, m, CH); 4.10 (2H, s, CH₂NH₂); 3.95–3.76 (2H, m, COCH ₂NH₂); 3.74–3.65 (1H, m, CH pip);3.12–2.96 (1H, m, CH pip); 2.84–2.58 (5H, m, 2×CH₂ ind, CH pip);2.26–2.07 (1H, m, CH pip); 2.04–1.84 (3H, m, CH₂ ind, CH pip); 1.79–1.69(1H, m, CH pip); 1.53–1.04 (2H, m, CH₂ pip).

HPLC (Luna 2, Gradient 1): rt=2.65 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.35 minutes, 464 (MH)⁺.

Example 160 3-(Aminomethyl)benzoyl-D/L-phenylglycinebenzothiazol-2-amide trifluoroacetate salt α-N-BOC-D/L-Phenylglycinebenzothiazol-2-amide

A solution of N-BOC-D-phenylglycine (750 mg, 3.0 mmol) in anhydroustetrahydrofuran (20 mL) was stirred at room temperature under argon.Isobutyl chloroformate (0.52 mL, 4.0 mmol) and diisopropylethylamine(0.81 mL, 4.7 mmol) were added and the solution was stirred for 30minutes. A solution of 2-aminobenzothiazole (500 mg, 3.3 mmol) intetrahydrofuran (10 mL) was added to the mixed anhydride solution andstirred overnight at room temperature. Ethyl acetate (50 mL) was addedand the organic phase was washed with water (25 mL), 5% HCl solution (25mL), saturated aqueous NaHCO₃ (25 mL) and water (25 mL), before beingdried (MgSO₄) and concentrated under reduced pressure. The residue waspurified by flash chromatography using ethyl acetate/hexane 1/1 aseluant to afford the coupled product as a yellow oil (785 mg, 68%).

¹H NMR (CDCl₃): 7.71 ppm (1H, d, J=7.2 Hz, Ar); 7.42 (1H, d, J=7.2 Hz,Ar); 7.36 (8H, m, Ar and NH); 6.29 (1H, br s, CH); 5.60 (1H, br s, NH);1.30 (9H, s, C₄H₉).

3-(N-BOC-Aminomethyl)benzoyl-D/L-phenylglycine benzothiazol-2-amide

A solution of the α-N-BOC-D/L-phenylglycine benzothiazol-2-amide (785mg, 2.24 mmol) in dichloromethane (5 mL) was treated withtrifluoroacetic acid (2 mL) and stirred for 1 hour at room temperature.The solution was concentrated under reduced pressure and the residualTFA salt was taken up in dimethylformamide (15 mL). This solution wastreated with triethylamine (0.92 mL, 6.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (478 mg, 2.5mmol), 3-(N-BOC-aminomethyl)benzoic acid (562 mg, 2.24 mmol) and DMAP(50 mg) and stirred overnight at room temperature. The solution waspartitioned between ethyl acetate (25 mL) and water (25 mL) and theorganic phase was washed with 5% HCl solution (25 mL), saturated aqueousNaHCO₃ (25 mL) and water (25 mL) before being dried (MgSO₄) andconcentrated under reduced pressure to afford a yellow oil. The residuewas purified by flash chromatography using ethyl acetate/hexane 1/1 aseluant to afford a colourless solid (185 mg, 16%).

¹H NMR (CDCl₃): 7.87–7.73 ppm (2H, m, Ar and NH); 7.66–7.45 (3H, m, Arand NH); 7.40–7.30 (3H, m, Ar); 7.26–7.00 (6H, m, Ar); 6.11 (1H, d,J=6.9 Hz, CHPh); 4.98 (1H, br s, NH); 4.02 (2H, d, J=6.5 Hz, CH ₂NH₂).

3-(Aminomethyl)benzoyl-D/L-phenylglycine benzothiazol-2-amidetrifluoroacetate salt

A solution of 3-(N-BOC-aminomethyl)benzoyl-D/L-phenyl-glycinebenzothiazol-2-amide (156 mg, 0.3 mmol) in dichloromethane (3 mL) wasstirred at room temperature and trifluoroacetic acid (2 mL) was added.Stirring was continued for a further hour and the solvents were removedunder reduced pressure to afford a yellow oil which was triturated withdiethyl ether to give the trifluoroacetate salt as a colourless solid(120 mg, 96%).

¹H NMR (d₄ methanol): 7.82–7.67 (3H, m, Ar); 7.56 (1H, d, J=7.2 Hz, Ar);7.53–7.21 (8H, m, Ar); 7.19–7.09 (1H, m, CHPh); 3.89 (2H, s, CH ₂NH₂).

HPLC (Luna 2, Gradient 1): rt=3.95 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.88 minutes, 417 (MH)⁺.

Examples 161–166 were prepared in a manner analogous to Example 160except that the indicated amine was used in place of2-aminobenzothiazole.

Example 161 3-(Aminomethyl)benzoyl-D/L-phenylglycine5,6-dimethylbenzothiazol-2-amide trifluoroacetate salt

From 2-amino-5,6-dimethylbenzothiazole.

¹H NMR (d₄ methanol): 7.80–7.63 ppm (2H, m, Ar); 7.47–7.07 (9H, m, Ar);5.71 (1H, s, CHPh); 3.92 (2H, s, CH ₂NH₂); 2.12 (6H, s, 2×CH₃).

HPLC (Luna 2, Gradient 1): rt=4.39 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.10 minutes, 445 (MH)⁺.

Example 162 3-(Aminomethyl)benzoyl-D/L-phenylglycine 6-methoxybenzothiazol-2-amide trifluoroacetate salt

From 2-amino-6-methoxybenzothiazole.

¹H NMR (CDCl₃): 8.18 ppm (3H, br s, Ar and NH); 7.90 (1H, s, Ar); 7.79(1H, s, Ar); 7.71 (1H, d, J=7.2 Hz, Ar); 7.63–7.28 (8H, m, Ar and NH);7.24 (1H, s, Ar); 7.10 (1H, d, J=7.2 Hz, Ar); 5.72 (1H, d, J=6.5 Hz,CHPh); 4.09 (2H, s, CH ₂NH₂); 3.88 (3H, s, OCH₃).

HPLC (Luna 2, Gradient 1): rt=4.26 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.94 minutes, 447 (MH)⁺.

Example 163 3-(Aminomethyl)benzoyl-D/L-phenylglycine6-methylbenzothiazol-2-amide trifluoroacetate salt

From 2-amino-6-methylbenzothiazole.

¹H NMR (d₄ methanol): 8.02–7.90 ppm (2H, m, Ar); 7.70–7.54 (6H, m, Ar);7.48–7.37 (3H, m, Ar); 7.25 (1H, d, J=7.2 Hz, Ar); 5.92 (1H, s, CHPh);4.19 (2H, s, CH ₂NH₂); 2.46 (3H, s, CH₃).

HPLC (Luna 2, Gradient 1): rt=4.21 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.26 minutes, 431 (MH)⁺.

Example 164 3-(Aminomethyl)benzoyl-D/L-phenylglycine4-methoxybenzothiazol-2-amide trifluoroacetate salt

From 2-amino-4-methoxybenzothiazole.

¹H NMR (d₄ methanol): 7.88 ppm (1H, d, J=7.2 Hz, Ar); 7.79 (1H, d, J=7.2Hz, Ar); 7.64–7.14 (9H, m, Ar); 6.94 (1H, d, J=7.2 Hz, Ar); 5.89 (1H, s,CHPh); 4.03 (2H, s, CH ₂NH₂); 3.93 (3H, s, OCH₃).

HPLC (Luna 2, Gradient 1): rt=3.95 minutes.

LC/MS (Luna 2, Gradient 4): rt=1.88 minutes, 447 (MH)⁺.

Example 165 3-(Aminomethyl)benzoyl-D/L-phenylglycine4-methylbenzothiazol-2-amide trifluoroacetate salt

From 2-amino-4-methylbenzothiazole.

¹H NMR (d₄ methanol): 7.95 ppm (1H, s, Ar); 7.89 (1H, d, J=7.2 Hz, Ar);7.69–7.33 (8H, m, Ar); 7.27–7.12 (2H, m, Ar); 5.91 (1. H, s, CHPh); 4.03(2H, s, CH ₂NH₂); 2.60 (3H, s, CH₃).

HPLC (Luna 2, Gradient 1): rt=4.31 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.18 minutes, 431 (MH)⁺.

Example 166 3-(Aminomethyl)benzoyl-D/L-phenylglycine4-chlorobenzothiazol-2-amide trifluoroacetate salt

From 2-amino-4-chlorobenzothiazole.

¹H NMR (d₄ methanol): 8.00–7.85 ppm (2H, m, Ar); 7.82–7.74 (1H, d, J=7.2Hz, Ar); 7.67–7.35 (8H, m, Ar); 7.25 (1H, t, J=7.2 Hz, Ar); 5.89 (1H, s,CHPh); 4.10 (2H, s, CH ₂NH₂).

HPLC (Luna 2, Gradient 1): rt=4.29 minutes.

LC/MS (Luna 2, Gradient 4): rt=2.05 minutes, 451 (MH)⁺.

Example 167 3-(Aminomethyl)benzoyl-DL-phenylglycinetetrahydrobenzothiazol-2-amide

From 4,5,6,7-tetrahydrobenzothiazol-2-amine, the synthesis of which isdescribed below.

4,5,6,7-Tetrahydro-1,3-benzothiazol-2-amine

A stirred mixture of 2-chlorocyclohexanone (200 mg, 1.5 mmol) andthiourea (114 mg, 1.5 mmol) in tetrahydrofuran (20 ml) was heated atreflux for 6 hours. The solution was concentrated under reduced pressureand the amine was purified by flash column chromatography usingethylacetate/hexane 1/1 as eluent to afford a colourless oil (169 mg,74%).

¹H NMR (CDCl₃): 5.06 (2H, br s, NH₂); 2.40–2.23 (4H, m, 2×CH₂);1.64–1.51 (4H, m, 2×CH₂).

3-(Aminomethyl)benzoyl-DL-phenylglycine tetrahydrobenzothiazol-2-amide

¹H NMR (d₄ methanol): 8.01–7.92 (2H, m, Ar); 7.68 (1H, d, J=7.2 Hz, Ar);7.61–7.51 (3H, m, Ar); 7.47–7.34 (3H, m, Ar); 5.90 (1H, s, CH); 4.20(2H, s, CH ₂NH₂); 2.69 (2H, br s, CH₂); 2.60 (2H, br s, CH₂); 1.98 (4H,br s, 2×CH₂).

HPLC (Luna 2, Gradient 1): rt=3.55 minutes. LCMS (Luna 2, Gradient 4):rt=1.88 minutes, 421 (M+H)⁺.

The compounds exemplified hereinabove have been found to be inhibitorsof tryptase by the method of Tapparelli et al., (1993) J. Biol. Chem.,268, 4734 to 4741.

1. A tryptase inhibitor compound of formula (I)

where: R₅ represents amino, hydroxy, aminomethyl, hydroxymethyl orhydrogen; R_(6a) represents hydrogen or methyl; X—X is selected from thegroup consisting of —CH═CH—, —CONR_(1a)—, —NH—CO—, —NR_(1a)—CH₂—,—CH₂—NR_(1a)—, —CH₂O—, —OCH₂—, —COO—, —OC═O— and —CH₂CH₂—; R_(1a)represents hydrogen, (1–6C)alkyl or phenyl(1–6C)alkyl; L is CO orCONR_(1d) (CH₂)_(m) in which m is 0 or 1 and R_(1d) is hydrogen,(1–6C)alkyl or phenyl(1–6C)alkyl; Cy is phenyl optionally substituted byR_(3a) or R_(3i)X_(i) in which X_(i) is a bond, O, NH or CH₂ and R_(3i)is phenyl optionally substituted by R_(3a); each R_(3a) independently ishydrogen, hydroxyl, (1–6C)alkoxy, (1–6C)alkyl, (2–6C)alkenyl,(2–6C)alkynyl, (1–6C)alkanoyl, (1–6C) alkylaminoalkyl,hydroxy(1–6C)alkyl, carboxy, (1–6C) alkoxyalkyl, (1–6C) alkoxycarbonyl,(1–6C) alkylaminocarbonyl, amino(1–6C)alkyl CONH₂, CH₂CONH₂,aminoacetyl, (1–6C)alkanoylamino, (1–6C) alkoxycarbonylamino, amino,halo, cyano, nitro, thiol, 1–6C) alkylthio, (1–6C) alkylsulphonyl,(1–6C) alkylsulphenyl, imidazolyl, hydrazido, (1–6C) alkylimidazolyl,(1–6C) alkylsulphonamido, (1–6C) alkylaminosulphonyl, aminosulphonyl,(1–6C) haloalkoxy, or (1–6C) haloalkyl; X_(i) is a bond, O, NH or CH₂;and R_(3i) is phenyl optionally substituted by R_(3a); and Lp is aheterocyclic group, or a combination of a heterocyclic group and one ormore alkyl, alkenyl, carbocyclic or heterocyclic groups linked by aspiro linkage or a single or double bond or by C═O, O, OCO, COO, S, SO,SO₂, CONR_(1e), NR_(1e)—CO— or NR_(1e) linkage (where R_(1e) is asdefined for R_(1a)), optionally substituted by one or more oxo or R₃groups in which R₃ is an amino acid residue, N-(1–6C)alkylaminocarbonyl,N,N-di(1–6C)alkylaminocarbonyl, N-(1–6C)alkylaminoalkanoyl,N-(1–6C)alkanoylamino(1–6C)alkanonyl, C-hydroxyamino(1–6C)alkanoyl,hydroxy(2–6C)alkanoylamino(1–6C)alkanoyl, di(1–6C)alkylaminosulfonyl,hydrogen, hydroxyl, (1–6C)alkoxy, (1–6C)alkanoyloxy, (1–6C) alkyl,(2–6C) alkenyl (2–6C)alkynyl, (3–6C)alkenyloxycarbonyl, (1–6C)alkanoyl,amino(1–6C)alkyl, amido (CONH₂), amino(1–6C)alkanoyl,aminocarbonyl(1–5C)alkanoyl, hydroxy(1–6C)alkyl, carboxy,hydroxy(1–6C)alkanoyl, (1–6C)alkoxy(1–6C)alkyl,(1–6C)alkoxycarbonyl(1–5C)alkyl, (1–6C)alkoxycarbonyl,(1–6C)alkanoylamino, amino, halo, cyano, nitro, thiol, (1–6C)alkylthio,(1–6C)alkylsulfonyl, (1–6C)alkylsulphenyl or hydrazido; or aphysiologically tolerable salt thereof.
 2. A compound as claimed inclaim 1, in which R₅ is amino or hydrogen.
 3. A compound as claimed inclaim 2, in which R₅ is hydrogen.
 4. A compound as claimed in claim 1,in which R_(6a) is hydrogen.
 5. A compound as claimed in claim 1, inwhich X—X is CONH.
 6. A compound as claimed in claim 1, in which thealpha carbon atom (*) has the conformation that would result fromconstruction from a D-α-aminoacid NH₂—CH(Cy)—COOH where the NH₂represents part of X—X.
 7. A compound as claimed in claim 1, in whichR_(3a) is hydrogen; hydroxyl; methoxy; ethoxy; isopropoxy; methyl;ethyl; isopropyl; acetyl; propanoyl; isopropanoy; methylaminomethyl;dimethylaminomethyl; hydroxymethyl; carboxy; methoxymethyl;methoxycarbonyl; ethoxycarbonyl; methylaminocarbonyl;dimethylaminocarbonyl; aminomethyl; CONH₂; CH₂CONH₂; aminoacetyl;formylamino; acetylamino; methoxycarbonylamino; ethoxycarbonylamino;t-butoxycarbonylamino; amino; fluoro; chloro; cyano; nitro; thiol;methylthio; methylsulphonyl; ethylsulphonyl; methylsulphenyl;imidazol-4-yl; hydrazido; 2-methylimidazol-4-yl; methylsulphonylamido;ethylsulphonylamido; methylaminosulphonyl; ethylaminosulphonyl;aminosulphonyl; trifluoromethoxy or trifluoromethyl; and R_(3i)X_(i) isphenyl, phenoxy, phenylamino or benzyl.
 8. A compound as claimed inclaim 7, in which Cy is phenyl, 4-aminophenyl, 3-hydroxyphenyl,4-methylphenyl, 2,4-dimethylphenyl, 3,6-dimethylphenyl, 4-ethylphenyl,4-isopropylphenyl, 4-hydroxphenyl, 3-aminomethylphenyl,4-aminomethylphenyl, 4-(H₂NCO)phenyl, 4-hydroxymethylphenyl,3-hydroxymethylphenyl, 2-hydroxymethylphenyl, 4-carboxyphenyl,4-isopropoxyphenyl, 2-chlorophenyl, 4-phenylphenyl or 4-phenoxyphenyl.9. A compound as claimed in claim 1, in which Cy represents anoptionally R_(3a) substituted phenyl group.
 10. A compound as claimed inclaim 9, in which R_(3a) is selected from: hydrogen, hydroxyl, methoxy,ethoxy, methyl, ethyl, methylaminomethyl, dimethylaminomethyl,hydroxymethyl, methoxymethyl, methylaminocarbonyl,dimethylaminocarbonyl, aminomethyl, CONH₂, CH₂CONH₂, aminoacetyl,formylamino, acetylamino, methoxycarbonylamino, ethoxycarbonylamino,t-butoxycarbonylamino, amino, fluoro, chloro, cyano, nitro, thiol,methylthio, methylsulphenyl, imidazol-4-yl, hydrazido,2-methylimidazol-4-yl, methylsulphonylamido, ethylsulphonylamido,methylaminosulphonyl, ethylaminosulphonyl, aminosulphonyl,trifluoromethoxy or trifluoromethyl.
 11. A compound as claimed in claim10, in which Cy is selected from the group consisting of phenyl,4-aminophenyl, 4-hydroxyphenyl, 3-aminomethylphenyl,4-aminomethylphenyl, 4-hydroxymethylphenyl, 3-hydroxymethylphenyl,2-hydroxymethylphenyl and 4-phenylphenyl.
 12. A compound as claimed inclaim 1, in which L represents CO, CONH, CONCH₃ or CONHCH₂.
 13. Acompound as claimed in claim 12, in which L is CO, CONH or CONCH₃.
 14. Acompound as claimed in claim 1, in which R₃ is selected from the groupconsisting of N-acetylalaninoyl; serinoyl; threoninoyl; aspartoyl;glutamoyl; N-(1,3-dimethyl)butylamino-carbonyl;N-methyl-N-ethylaminocarbonyl; N-methylaminoacetyl;2-N-acetylaminoacetyl; 2-N-acetylaminopropanoyl;2-N-(2-methylpropanoyl)aminoacetyl; 2-amino-3hydroxypropanoyl;2-amino-3-hydroxybutanoyl; 2-hydroxyacetylaminoacetyl;dimethylaminosulfonyl; hydrogen; hydroxyl; methoxy; acetoxy; methyl;ethyl; propyl; 2-propyl; 2,2-dimethylethyl; allyl; propynyl;allyloxycarbonyl; acetyl; propionyl; isobutyryl; aminomethyl; CONH₂;aminoacetyl; aminopropionyl; 2-aminopropionyl; aminocarbonylacetyl;hydroxymethyl; 1-hydroxyethyl; carboxy; 2-hydroxyacetyl;2-hydroxypropanoyl; methoxymethyl; methoxycarbonylmethyl;methoxycarbonyl; ethoxycarbonyl; formylamino; acetylamino; amino;chloro; cyano; nitro; thiol; methylthio; methylsulphonyl; ethylsulfonyl;methylsulphenyl; and hydrazido.
 15. A compound as claimed in claim 5, inwhich in which L represents CO and Lp represents


16. A compound as claimed in claim 15, in which R₃ represents hydrogen,hydroxyl or (1–6C)alkylaminocarbonyl.
 17. A compound as claimed in claim5, in which L represents CONH and Lp represents

in which X is CH or N.
 18. A compound as claimed in claim 17, in whicheach R₃ is selected independently from the group consisting of hydrogen,amino, hydroxy, (1–6C)alkyl, (1–6C)alkanoyl, (1–6C)alkanoyloxy,(1–5C)alkoxycarbonyl(1–6C)alkyl, amino(1–6C)alkyl and cyano.
 19. Acompound as claimed in claim 5, in L represents CONR_(1d) and Lprepresents

in which R_(3x) represents R₃ or a group of formula—(X_(1y))_(p)-(G₁)-R_(j) in which p is 0 or 1 ; X_(1y) represents CO,COO, CONH or SO₂; G₁ represents (1–3C)alkanediyl, CH₂OCH₂ or, when p is1, a bond; and R_(j) represents a carbocyclic or heterocyclic group,optionally substituted by R₃.
 20. A compound as claimed in claim 19, inwhich L represents CONH and R_(3x), represents R₃ or a group of formula—(CO)_(p)-(G₁)-R_(j) in which p is 0 or 1; G₁ represents(1–3C)alkanediyl or, when p is 1, a bond; and R_(j) represents acarbocyclic or heterocyclic group, optionally substituted by R₃.
 21. Acompound as claimed in claim 19, in which Lp is selected from

in which (i) when R₃ is a substituent on the 1-position of a2,3-dihydroindolyl group, it represents an amino acid residue;(1–6C)alkylaminocarbonyl; N-(1–6C)alkylamino(1–6C)alkanoyl;N-alkanoylaminoalkanonyl; C-hydroxyamino(1–6C)alkanoyl;hydroxy(1–6C)alkanoylamino(1–6C)alkanoyl; di(1–6C)alkylaminosulfonyl;hydrogen; (1–6C)alkyl; (1–6C)alkanoyl; (1–6C)alkoxycarbonyl;(1–6C)acyloxymethoxycarbonyl; amino(1–6C)alkyl; amido(CONH₂);amino(1–6C)alkanoyl; aminocarbonyl(1–6C)alkanoyl; hydroxy(1–6C)alkyl;hydroxy(1–6C)alkanoyl; (1–6C)alkoxy(1–6C)alkyl;(1–6C)alkoxycarbonyl(1–6C)alkyl; (1–6C)alkoxycarbonyl;(1–6C)alkanoylamino; or (1–6C)alkylsulfonyl; and (ii) when R₃ is asubstituent on a cyclohexyl, phenyl, naphthyl, thiazolyl, imidazolyl,pyridyl or quinolinyl group, it is hydrogen, hydroxy, amino,alkanoylamino, alkyl, aminoalkyl or alkanoylaminoalkyl.
 22. Apharmaceutical composition, which comprises a compound as claimed inclaim 1 together with at least one pharmaceutically acceptable carrieror excipient.
 23. A method of treatment of the human or non-human animalbody to combat a condition responsive to a tryptase inhibitor, whichcomprises administering to said body an effective amount of a compoundas claimed in claim
 1. 24. A method of treatment of the human ornon-human animal body to combat a condition selected from asthma,allergic rhinitis, eczema, psoriasis, atopic dermatitis, urticaria,rheumatoid arthritis, conjunctivitis, inflammatory bowel disease,neurogenic inflammation, and atherosclerosis, which comprisesadministering to said body a compound of formula (I)

where: R₅ represents amino, hydroxy, aminomethyl, hydroxymethyl orhydrogen; R_(6a) represents hydrogen or methyl; X—X is selected from thegroup consisting of —CH═CH—, —CONR_(1a)—, —NH—CO—, —NR_(1a)—CH₂—,—CH₂—NR_(1a)—, —CH₂O—, —OCH₂—, —COO—, —OC═O— and —CH₂CH₂—; R_(1a)represents hydrogen, (1–6C)alkyl or phenyl(1–6C)alkyl; L is CO orCONR_(1d) (CH₂)_(m) in which m is 0 or 1 and R_(1d) is hydrogen,(1–6C)alkyl or phenyl(1–6C)alkyl; Cy is phenyl optionally substituted byR_(3a) or R_(3i)X_(i) in which X_(i) is a bond, O, NH or CH₂ and R_(3i)is phenyl optionally substituted by R_(3a); each R_(3a) independently ishydrogen, hydroxyl, (1–6C)alkoxy, (1–6C)alkyl, (2–6C)alkenyl,(2–6C)alkynyl, (1–6C)alkanoyl, (1–6C)alkylaminoalkyl,hydroxy(1–6C)alkyl, carboxy, (1–6C)alkoxyalkyl, (1–6C)alkoxycarbonyl,(1–6C) alkylaminocarbonyl, amino(1–6C)alkyl CONH₂, CH₂CONH₂,aminoacetyl, (1–6C)alkanoylamino, (1–6C)alkoxycarbonylamino, amino,halo, cyano, nitro, thiol, (1–6C)alkylthio, (1–6C) alkylsulphonyl,(1–6C)alkylsulphenyl, imidazolyl, hydrazido, (1–6C)alkylimidazolyl,(1–6C)alkylsulphonamido, (1–6C) alkylaminosulphonyl, aminosulphonyl,(1–6C) haloalkoxy, or (1–6C) haloalkyl; and Lp is a heterocyclic group,or a combination of a heterocyclic group and one or more alkyl, alkenyl,carbocyclic or heterocyclic groups linked by a spiro linkage or a singleor double bond or by C═O, O, OCO, COO, S, SO, SO₂, CONR_(1e),NR_(1e)—CO— or NR_(1e) linkage (where R_(1e) is as defined for R_(1a)),optionally substituted by one or more oxo or R₃ groups in which R₃ is anamino acid residue, N-(1–6C)alkylaminocarbonyl,N,N-di(1–6C)alkylaminocarbonyl, N-(1–6C)alkylaminoalkanoyl,N-(1–6C)alkanoylamino(1–6C)alkanonyl, C-hydroxyamino(1–6C)alkanoyl,hydroxy(2–6C)alkanoylamino(1–6C)alkanoyl, di(1–6C)alkylaminosulfonyl,hydrogen, hydroxyl, (1–6C)alkoxy, (1–6C)alkanoyloxy, (1–6C)alkyl,(2–6C)alkenyl (2–6C)alkynyl, (3–6C)alkenyloxycarbonyl, (1–6C)alkanoyl,amino(1–6C)alkyl, amido(CONH₂), amino(1–6C)alkanoyl,aminocarbonyl(1–5C)alkanoyl, hydroxy(1–6C)alkyl, carboxy,hydroxy(1–6C)alkanoyl, (1–6C)alkoxy(1–6C)alkyl,(1–6C)alkoxycarbonyl(1–5C)alkyl, (1–6C)alkoxycarbonyl,(1–6C)alkanoylamino, amino, halo, cyano, nitro, thiol, (1–6C)alkylthio,(1–6C)alkylsulfonyl, (1–6C)alkylsulphenyl or hydrazido; or aphysiologically tolerable salt thereof.
 25. A method as claimed in claim24, in which R₅ is hydrogen; R_(6a) is hydrogen; X—X is CONH; and R₃ isselected from the group consisting of N-acetylalaninoyl; serinoyl;threoninoyl; aspartoyl; glutamoyl; N-(1,3-dimethyl)butylamino-carbonyl;N-methyl-N-ethylaminocarbonyl; N-methylaminoacetyl;2-N-acetylaminoacetyl; 2-N-acetylaminopropanoyl;2-N-(2-methylpropanoyl)aminoacetyl; 2-amino-3-hydroxypropanoyl;2-amino-3-hydroxybutanoyl; 2-hydroxyacetylaminoacetyl;dimethylaminosulfonyl; hydrogen; hydroxyl; methoxy; acetoxy; methyl;ethyl; propyl; 2-propyl; 2,2-dimethylethyl; allyl; propynyl;allyloxycarbonyl; acetyl; propionyl; isobutyryl; aminomethyl; CONH₂;aminoacetyl; aminopropionyl; 2-aminopropionyl; aminocarbonylacetyl;hydroxymethyl; 1-hydroxyethyl; carboxy; 2-hydroxyacetyl;2-hydroxypropanoyl; methoxymethyl; methoxycarbonylmethyl;methoxycarbonyl; ethoxycarbonyl; formylamino; acetylamino; amino;chloro; cyano; nitro; thiol; methylthio; methylsulphonyl; ethylsulfonyl;methylsulphenyl; and hydrazido.
 26. A method as claimed in claim 24, inwhich Cy represents an optionally R_(3a) substituted phenyl group; andR_(3a) is selected from: hydrogen, hydroxyl, methoxy, ethoxy, methyl,ethyl, methylaminomethyl, dimethylaminomethyl, hydroxymethyl,methoxymethyl, methylaminocarbonyl, dimethylaminocarbonyl, aminomethyl,CONH₂, CH₂CONH₂, aminoacetyl, formylamino, acetylamino,methoxycarbonylamino, ethoxycarbonylamino, t-butoxycarbonylamino, amino,fluoro, chloro, cyano, nitro, thiol, methylthio, methylsulphenyl,imidazol-4-yl, hydrazido, 2-methylimidazol-4-yl, methylsulphonylamido,ethylsulphonylamido, methylaminosulphonyl, ethylaminosulphonyl,aminosulphonyl, trifluoromethoxy or trifluoromethyl.
 27. A method asclaimed in claim 24, in which the condition is asthma.